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A MANUAL OF GENERAL PATHOLOGY 



A MANUAL OF 

GENERAL PATHOLOGY 



FOR STUDENTS 



BY 

SIDNEY MARTIN, M. D., F. R. S., F. R. C. P. 

PROFESSOR OF PATHOLOGY AT UNIVERSITY COLLEGE ; PHYSICIAN TO UNIVERSITY 
COLLEGE HOSPITAL, LONDON 



WITH NUMEROUS WOODCUTS FROM MICRO-PHOTOGRAPHS AND OTHER ILLUSTRA- 
TIONS. INCLUDING MANY IN COLORS 



PHILADELPHIA 

P. BLAKISTON'S SON & CO., 

1012 WALNUT STREET 
I904 






LIBRAE/ of CONGRESS 
Two Copies Received 



JAN 20 1904 

. Copyright Entry 

&o-. r-/ * 9 d 

CLASS «t XXo. No. 



Copyright, 1903, by 
P. BLAKISTON'SlSON & CO. 



THE MERSHON COMPANY PRESS 
RAHWAY, N. J. 



PREFACE 

The basis of this Text-book has been the Lectures on General 
Pathology delivered at University College during the past five 
or six years. It attempts to give in a short space a clear 
account of the processes of disease, which it is necessary for 
the student to appreciate in order to follow the study of scien- 
tific medicine. The study of General Pathology must go hand 
in hand with that of medicine and be preceded by practical 
work in Morbid Histology and Anatomy, and to some extent 
in Bacteriology. These subjects are in the book only dealt with 
as far as they have an evidently direct bearing on the processes 
of disease. Illustrations of some of the minute changes occur- 
ring in diseased processes have been included, in order to 
remind the student of the structural changes occurring with 
disordered function. These illustrations and descriptions are, 
however, not intended to take the place of a systematic study 
of Morbid Histology. References to the literature of the 
subject have been purposely omitted. I wish, however, to 
acknowledge my indebtedness more particularly to Cohnheim's 
Vorlesungen iiber allgemeine Pathologie; Cohnheim's Gesam- 
melte Abhandlungen; some articles in Clifford Allbutt's Sys- 
tem of Medicine; von Noor den's Lehrbuch der Pathologie des 
Stoifwechsels; Cabot's Clinical Examination of the Blood; 



viii PREFACE 

and Mott's Croonian Lectures on the Degeneration of the 
Neuron. I am indebted to Professor J. Risien Russell, M. D., 
for valuable criticism of the Chapter on the Nervous System; 
to my Assistant, Dr. D. N. Nabarro, Assistant Professor of 
Pathology in University College, for valuable help in reading 
the proofs ; to Professor G. D. Thane, for the outline diagrams 
of Figs. 47 to 50 and Fig. 101 ; to Mr. Renshaw for permission 
to use Fig. 125; to Dr. F. W. Mott, F. R. S., for permission to 
use the figures illustrating the Chapter on the Nervous System. 
The remaining illustrations (unless where acknowle.dged in 
the text) are from photographs by Mr. E. S. Worrall, 
Radiographer at University College Hospital. 

Sidney Martin. 

August, 1903. 






CONTENTS 



CHAPTER I 



INFLAMMATION 



Changes Occurring in Inflammation, 
Exudation of Liquid, 
Diapedesis. .... 

Effect of Inflammation on Tissues, 
Varieties of Inflammation. 
Course of Inflammation, 
Inflammation of Non-vascular Tissues 
Phagocytosis. ..... 



PAGE 

I 

7 

9 

ii 

12 
20 

24 
27 



CHAPTER II 

CHANGES IN THE BODY TEMPERATURE IN DISEASE; PYREXIA 

Normal Temperature. ......... 35 

Pyrexia, ............ 37 

Pathological Changes 38 

Causes, ............ 46 



CHAPTER III 

INFECTION 

I. The Infective Agent 



Hyphomycetes, . 
Blastomycetes, . 



5i 

53 



IX 



CONTENTS 



Bacteria, 

Conditions of Growth, 

Variability in Virulence, 



54 
60 

65 



CHAPTER IV 

infection {continued) 

2. Chemical Products of Bacteria and their Action 

Simple Bacterial Fermentation, . . . . . -69 

Nitrification. ........... 71 

Putrefaction. ........... 71 

Toxins, ............ 74 

Products of Individual Bacteria, ....... 77 

General Action of Products, 104 



CHAPTER V 



infection (continued) 



3. The Infective Process 



Proof of Infection, . 
Sources of Infection. 
Modes of Infection. . 
Course of Infection. . 
Examples of Infective Processes 
Anthrax, .... 
Pus Infection, . 
Tuberculosis, 

Syphilis, .... 
Intestinal Infections. 
Malaria, .... 
Malignant New Growths, . 



108 

113 
114 
116 
121 
121 
122 
127 
140 
141 
147 
152 



CONTENTS 



XI 



CHAPTER VI 

infection {continued) 

4. Immunity 

PAGE 

Definition. 157 

Natural Immunity. . . . . . . . . .158 

Natural Defenses of the Body 161 

Artificial Immunity, .......... 165 

Vaccinia, ............ 165 

Anthrax. ............ 169 

Cholera, ............ 170 

Plague . . . .171 

Typhoid Fever, ........... 171 

Hydrophobia. . . . . . . . . . . .172 

Bacillus Pyocyaneus, ......... 174 

Diphtheria, 175 

Tetanus. ............ 177 

Ricin and Abrin, 177 

The Blood and Tissues in Immunity. ...... 178 

Relation of Toxin and Antitoxin, 179 

Agglutinins and Bacteriolysins, ....... 186 

Coagulins and Precipitins, ........ 190 

Cytotoxins, 190 

Summary, ........... 191 



CHAPTER VII 



OX THE DEGENERATION AND REGENERATION OF CELLS AND TISSUES 



The Normal Cell and its Secretions. . 

Cloudy Swelling, ...... 

Fatty Degeneration. ...... 

Albuminoid Degeneration; Zenker's Degeneration. 
Mucinoid Degeneration, ..... 

Colloid Degeneration, ..... 



194 
196 
197 
209 
211 
212 



xii 


CONTENTS 


PAGE 


Dropsical Degeneration, 




. 212 


Atrophy, . . . . 




. 212 


Necrosis, . 




. 214 


Fibrosis, . 




. 220 


Regeneration of Tissues, . 




227 



CHAPTER VIII 



CHANGES IN THE CIRCULATION IN DISEASE 



Normal Circulation, . 

Effect of Disease of the Heart, . 

Effect of Disease of the Pericardium, 

Effect of Disease of the Heart Muscle, 

Dilatation and Hypertrophy, 

Effect of Valvular Lesions, 

Changes in Cardiac Force and Rate, . 

Effect of Arterial Disease on the Circulation, 

Measurement of Blood Pressure, 

Causes of Arterial Degeneration, 



231 
233 
234 
236 

239 
242 
248 

254 
260 
261 



CHAPTER IX 

CHANGES IN THE CIRCULATION; EDEMA AND DROPSY 

Composition of Lymph, ......... 263 

Composition of Edema Fluids, ........ 264 

Formation of Lymph, . . 266 

Causes of Edema, 269 

CHAPTER X 

CHANGES IN RESPIRATION IN DISEASE 



Normal Respiration, . 
Disordered Respiration, 



277 
279 



CONTENTS 



xiu 



Changes in Respiratory Apparatus', . 
Influence of Pulmonary Circulation, . 
Influence of Composition of Blood. . 
Influence of Nervous System, . 
Compensation in Disordered Respiration, 
Modified Respiratory Acts, 



281 
285 
287 
288 
290 
293 



CHAPTER XI 

CHANGES IN THE BLOOD IN DISEASE 

I. Changes in the Red and White Corpuscles 



Normal Red Corpuscles, . 
Changes in Red Corpuscles in Disease, 
Blood in Anemias, 
The White Corpuscles, 
Leukocytosis, .... 
Leukemia. .... 

Origin of the White Corpuscles, 



298 
300 
303 
307 
310 
315 
319 



CHAPTER XII 

CHANGES IN THE BLOOD IN DISEASE (continued) 

2. Changes in the Hemoglobin; Hemolysis, Hemoglobinemia 

Changes in Hemoglobin, ......... 323 

Causes of Hemoglobinemia, ........ 325 

Hemolysis, ........... 326 

Hemoglobinuria. .......... 330 



CHAPTER XIII 

CHANGES IX THE BLOOD IN DISEASE {continued) 

3. Coagulability of the Blood in Disease — Thrombosis — Embolism 

Chemistry of Coagulation. ........ 

Intravascular Coagulation and Fluidity, 



331 
332 



xiv CONTENTS 

PAGE. 

Thrombosis, ........... 334 

Changes in Thrombi. . . . . . . . . 337 

Occurrence of Thrombosis in Disease, • . . . . . 338 

Causes of Thrombosis, 341 

Embolism, ........... 345 

Results of Thrombosis and Embolism, 348 

Air Embolism, . . . . . . . . . . 353 

Fat and other Forms of Embolism, ....... 354 



CHAPTER XIV 

HEMORRHAGE AND PIGMENTATION 

Causes of Hemorrhage, . . . . . . . . ' . 355 

Effect of Blood Pressure, ......... 357 

Effect of Disease of Vessel Wall, . 358 

Results of Hemorrhage, ......... 363 

Pigmentation 366 



CHAPTER XV 

THE EFFECTS OF DISEASE OF THE LIVER 

Jaundice, 368 

Influence of Jaundice on Metabolism, 375 

Variations in the Secretion of Bile, . . . . . . . 2>77 

Cholelithiasis, 378 

Disordered Functions of the Liver, 382 



CHAPTER XVI 

THE EFFECTS OF DISEASE OF THE KIDNEYS 

Functions of the Kidney, . . . . ... . . . 387 

Destruction of the Kidney Substance in Disease, .... 389 

Effects of Bright's Disease, 390 

Uremia, 393 



CONTENTS 



xv 



Changes in Metabolism in Kidney Disease 
Changes in the Urine in Disease, 
Pigments in the Urine, 
Aromatic Substances in the Urine, 
Blood and Bile in the Urine. 
Albuminuria, .... 
Albumosuria, .... 



PAGE 

394 
397 
402 

403 
405 
405 
408 



CHAPTER XVII 



THE EFFECT OF DISEASE OF THE DUCTLESS GLANDS OF THE BODY 

General Considerations, 
Thyroid Gland, 
Experimental Myxedema, . 
Action of Thyroid Extract, 
Pituitary Body, 
Suprarenal Bodies, . 
Action of Suprarenal Extract, 



410 
411 

413 
414 

417 
419 
421 



CHAPTER XVIII 



CHANGES IN METABOLISM 

General Considerations. ..... 

Changes in Metabolism due to Food, 
Changes due to Altered Processes of Digestion, 
Changes in the Metabolism in the Tissues, 
Uric Acid, ....... 

Glycosuria and Diabetes, ..... 

Fat Metabolism. 

Metabolism in Disorders of Respiration and Circulation, 
Metabolism in Anemias and Leukemia, 



424 
429 
433 
436 
436 
442 
448 
449 
452 



XVI 



CONTENTS 



CHAPTER XIX 



CHANGES IN THE NERVOUS SYSTEM IN DISEASE 



Arrangement of the Nervous System, 

Conditions of Nutrition of the Neurons, . 

Anatomical Results of Injury of a Neuron, 

Chemical Changes in Nerve Degeneration, 

Diseases of the Neurons, . 

Effects of Diseases of the Neurons, . 

Tremor and Spasm, .... 

Effect of Changes in the Circulation, 

Causation of Degeneration, . 

Effect of Nerve Disease on the Body and on Metabol 



PAGE 

457 
461 

465 
468 
470 
483 
489 
491 
492 
494 



Index, 



497 



INTRODUCTION 



General Pathology is a study of the processes of disease; 
Pathological Histology deals with structural changes in the 
tissues in disease, and bears the same relation to General 
Pathology as Histology bears to Physiology. Gross Morbid 
Anatomy is a study, not only of the naked-eye characters of 
disease, but more particularly of the distribution of the lesions 
produced by disease; that is, of their regional pathology. By 
this means much information may be gained as to the locality 
of origin of disease and of its mode of spread. Bacteriology 
includes a study of the living agents which frequently are the 
causes of disease, and by the investigation of the life history 
of these agents, and of the chemical changes produced by 
them, much information is gained as to the processes of 
infective disease. 

The study of General Pathology is carried out by the 
methods in use in Physiology; mainly by experiment with 
the view of elucidating the chemical, electrical, fermentative, 
and other changes which occur during the processes of disease. 
Experiment is of prime importance in the study of Pathology. 
( i ) By removal of healthy tissues or organs, not only is light 
thrown on their normal functions, but the study of the effects 
of their destruction by disease can be regulated. In this way 
great progress has been made in both Physiology and Pathol- 
ogy by removal of the thyroid, spleen, kidneys, liver, and 
portions of the brain. The study of the functional defects 
produced by the removal of these organs has aided in eluci- 
dating diseased conditions. (2) A second class of experiment 
is one in which a study is made of the results of separating 



xviii INTRODUCTION 

important parts either from the central nervous system or 
from the vascular system. In this way a change is produced 
in the functions of the part. (3) Stimulation of normal 
organs, mechanically, chemically, or by electricity, is also a 
means of determining the functions of organs; as, for ex- 
ample, the brain, secretory glands, and the heart. (4) The 
enormous advance made in the study of infective disease has 
occurred almost solely by experiment — namely, by the culti- 
vation of the infective agent outside the body, by the study 
of its chemical life processes, and by the investigation of the 
effects of introducing the living agent itself, or its chemical 
poisons, into animals. 

Disease is a variation from health or from the normal. 
It is produced by many different causes, the majority of 
which, however, are external agencies. A provisional classi- 
fication of diseased conditions as to their causation is as 
follows : 

1. Congenital disease, as in (a) Malformations and mons- 
trosities; (b) Fetal remnants. 

2. Acquired disease, which is mainly due to the following 
exter ial agencies: (a) heat, cold, and electric shock; (b) 
Mechanical injuries; (c) Chemical poisons; (d) Infective 
agents; (e) Alterations in the food; and (/) in the surround- 
ings of life as affecting the amount of oxygen taken into 
the body and the amount of muscular and mental activity. 
Of a similar nature are such conditions as excessive activity 
of any tissue or organ which is induced by external condi- 
tions. 

3. Inherited disease, (a) A defect in any particular tissue 
may be inherited, from which disease is brought out either 
by the surroundings of life or by the results of the process 
of infection. This particularly applies to the inheritance of 
defects in the nervous system. It is also shown, however, in 
the inheritance of defects in metabolism or in the tendency 
to specific infections, such as tuberculosis; (b) The disease 
itself may be inherited; either an infection such as syphilis, 
a defect in metabolism, or a special disease of the nervous 
system. 



INTRODUCTION xix 

In studying the processes of disease, although for con- 
venience the subject is divided into chapters, defect in one 
organ affects the body generally. Special conditions arise in 
which the disease becomes localised; in other cases it becomes 
generalized. Disease of an organ may, however, be of such 
a kind and degree as to produce no effect on the body generally, 
in the majority of instances compensation occurring. The 
introduction into the body of a foreign agent, living or dead, 
may result in local disease, owing to the resistance of the 
tissues; or the diseased condition may become general- 
ized. The diseased conditions produced, more particularly 
by the growth of living infective agents in the body, must 
be considered apart from other diseased conditions which 
result from injury to organs and tissues. The infective process 
lasts only a certain time in the body and may cease without 
leaving any permanent effect on the tissues. It may, how- 
ever, lead to damage of one or other tissue, this damage per- 
sisting and producing its own effects on the body. The effect 
of damage to organs has therefore to be considered, apart from 
infection. Thus the effects, both local and general, have to be 
considered of disease and disorder of the circulatory system; 
of the respiratory system; of the glands of the body, oi those 
with and of those without ducts; and of the nervous system, 
as well as of the changes which occur in the blood and other 
liquids in the body. 



GENERAL PATHOLOGY 



CHAPTER I 

INFLAMMATION 

Inflammation has been defined in the following terms : 
M The process of inflammation is the succession of changes 
which occurs in living tissue when it is injured, provided that 
the injury is not of such a degree as at once to destroy its 
structure and vitality" (Burdon Sanderson). Another defini- 
tion considers inflammation " as the series of changes con- 
stituting the local manifestation of the attempt at repair of 
actual or referred injury to a part, or, briefly, as the local 
attempted repair of actual or referred injury " (Adami). 

It is, however, impossible to give a succinct and complete 
definition of the process of inflammation, and to bring a 
definition into line with the researches which have been 
done of late years on the processes of infection, inflammation 
can most usefully be considered as a reaction of the tissues 
to the irritant effect of an injury, mechanical, chemical, ther- 
mal, or bacterial. 

Changes in Inflammation. — For many years inflammation 
was considered only as a phenomenon occurring in vascular 
tissues and in the higher animals, but research has shown 
that some of the changes may occur in non-vascular tissues 
and in invertebrata, and the study of these changes has greatly 
aided in the explanation of the phenomena of inflammation in 
tissues supplied by blood vessels. The phenomena of inflam- 



2 INFLAMMATION 

mation in vertebrata are well expressed in the four words, 
rubor (redness), tumor (swelling), dolor (pain), color (heat) 
(Celsus). To these, which accurately describe the more 
obvious features of inflammation, must be added functio Icesa, 
or diminished function. The predominance of one or other of 
these obvious changes depends on the intensity and character 
of the inflammation. 

The minute changes in inflammation may be observed 
occurring in the frog's mesentery or tongue. In performing 
this experiment the frog must be curarized and pithed, and 
the mesentery drawn out through an incision in the body wall, 
and pinned on a flat piece of cork which has a round hole 
cut in it. It may then.be placed on the stage of the micro- 
scope, and examined with a low power. The mere exposure 
of the delicate vascular membrane to the air excites inflamma- 
tory changes. 

The first obvious change is a dilatation of the blood vessels, 
both arteries and veins, with an increase in the rate of, the 
blood stream (active hyperemia). 

The second change is a slowing of the circulation, chiefly 
in the veins and capillaries, which ends in a condition of stasis, 
or stoppage in the capillaries. 

The third change observed is the collection of the white 
corpuscles at the periphery of the blood stream. They collect 
in such numbers in the slowed stream as to present the appear- 
ance of what is called " pavementing." 

The changes which occur in the visibility and arrange- 
ment of the blood corpuscles during the slowing of the blood 
stream are very characteristic. In the normal stream through 
a small vessel the current is seen to be divided into two 
parts. In the center is the axial stream of red blood cor- 
puscles, and between these and the vessel wall is the plasma 
of the blood, in which white corpuscles are moving along 
(Fig. i). The red corpuscles are not visible, owing to the 
rapidity of the stream. When the stream becomes slowed, 
the first change, observed at the same time as the collection 
of white corpuscles along the vessel wall, is the individual 
distinctness of the red corpuscles (Fig. 2). They still, how- 



CHANGES IN THE BLOOD STREAM 



* a 

: i 



Fig. i. 




B M MMm M ^ &® MM 1 M 



Fig. 2. 




Fig. 3. 




Microscopical Appearance of the Bloodstream of Different Velocities. 

Fig. r represents a vessel in rapid circulation. There is a well-defined red axial 
stream (a), in which the individual red copuscles are not distinguishable, and a periph- 
eral plasma zone (b), in which a few leukocytes are present. 

Fiir. 2 shows slight slowing of the blood stream in a vein. In the axial stream (a), 
the individual red corpuscles are seen, but noc distinctly. In the plasma zone (d) are 
numerous white corpuscles— pavementing of the leukocytes. 

Fig. 3 shows great slowing of the circulation. The axial stream is still present, 
but the individual red corpuscles are distinguishable. In the plasma zone there are 
few leukocytes, but numerous blood plates. 

Fig. 4 represents stagnation or stasis. At A, circulation has ceased; and at a and 
b, a red hyaline thrombus has formed. At B the vessel communicates with another, 
through which blood is still flowing, and from which come blood plates (c) into the 
stagnating blood. The red corpuscles and the blood plates are both undergoing 
changes in shape. (Eberth and Schimmelbusch.) 



4 INFLAMMATION 

ever, if the stream is not much slowed, preserve their axial 
direction. In greater slowing of the stream, as well as in 
the condition of stasis, the axial stream breaks up so that 
the red corpuscles become irregularly distributed (Figs. 3 and 
4). Some are seen flat, others sideways, and still others com- 
mencing to form rouleaux. 

During this time two other phenomena have taken place, 
namely, the emigration of the white corpuscles and the exuda- 
f ion of liquid. The emigration of the white corpuscles, as 
far as can be seen in such an experiment, takes place chiefly 
where there is not complete stasis of the blood stream. The 
corpuscles are noticed to adhere to the inner side of the vessel 
wall, and, if one corpuscle be watched, it is seen in a short 
time to form a slight projection on the outside of the vessel 
wall, and then gradually to protrude more and more from the 
vessel, which it eventually leaves with a little jerk (Fig. 5). 
Outside the vessel wall it shows ameboid movement, and 
passes into the loose connective tissue between the folds of the 
peritoneum. The red corpuscles pass out of the vessel in 
small numbers. Their emigration is not of the active char- 
acter of the ameboid corpuscle. As the process goes on the 
inflamed part swells, owing to the exudation of liquid. 

The redness of the inflamed part is due to the increased 
quantity of blood which goes to it, and this increased quantity 
of blood, as well as the exudation of liquid, leads to the swell- 
ing. The pain is due to the irritation of the nerve endings 
produced by the tension in the part and by specific poisons. 
The increased heat of the part is mainly due to the increased 
quantity of blood, the heat of which is not, as in normal con- 
ditions, distributed to other parts and so equalized, on account 
of the sluggishness of the blood stream. There is no increased 
formation of heat in the inflamed part. The rise of tempera- 
ture in it is not more than i° or 2° C. 

Causes of the Changes in Inflammation. — Changes in the 
Blood Vessels. — The increased flow of bfbod in the inflamed 
part is frequently spoken of as active hyperemia or as deter- 
mination of blood to the part. The changes in the blood 



CHANGES IN THE BLOOD VESSELS 5 

vessels accompanying this phenomenon were the subject of ex- 
tended research by Cohnheim and his pupils. As a result of 
this work it was concluded that the vessel wall was directly 
affected in inflammation, and that this accounted for the 




Fig. 5. — Emigration of leukocytes. 

The reproduction of the drawing shows dilatation of the capillaries in the frog's 
tongue, with irregularity of their contour, owing to exposure to air. In one capillary 
individual red corpuscles can be seen, and outside the capillaries are to be seen numer- 
ous leukocytes, which have emigrated from the blood vessels. Some of these are free 
in the tissue, others are attached to the vessel wall, and still others are seen just sepa- 
rating from the vessel wall. ^From the original figure by Aug. Waller, M. D., F/iil. 
Mag. y 1846.) 

changes in the blood vessels, the emigration of leukocytes, and 
the exudation of liquid. Arnold thought that stigmata formed 
between the endothelial cells, to allow of the emigration of the 
corpuscles. The endothelial cells undoubtedly undergo changes 
in inflammation. They show signs of irritation, as is evident 



6 INFLAMMATION 

from their enlargement and the karyokinesis of the nucleus. 
Some of Cohnheim's experiments indicate that interference 
with the nutrition of the vessel wall may lead to some of the 
phenomena of inflammation. Thus, if the blood supply to- 
the tongue of the frog be stopped for a short time, a temporary 
engorgement follows the return of the blood to the part. If, 
however, the vessel is compressed for a long time, inflamma- 
tion ensues when the pressure is removed. Again, the ear of 
a rabbit was bandaged for a few minutes, so as to press the 
blood away from the part. On removing the bandage and 
placing the ear in warm water (50°-6o° C), sudden and rapid 
inflammation ensued. 

In both these cases it may be supposed that the injury 
which led to the inflammation was the damage to the part 
which followed the deprivation of blood for a certain time. 
These experiments, however, do not explain why, in the 
first instance, there is dilatation of the blood vessels with 
increased rate of the blood stream, and, later, there are slowing 
and stasis. The blood vessels dilate and contract under the 
influence of their proper nerves, vaso-dilator and vasocon- 
strictor, and the influence of the nervous system must be con- 
sidered in relation to the process of inflammation and the 
changes in the blood vessels. 

The changes in inflammation may be purely local, and 
may occur when the influence of the central nervous system 
is removed, as in the pithed frog. The removal of nervous 
influence predisposes to inflammation, as is seen in the prone- 
ness of paralyzed parts to inflammation. This is associated' 
with a diminution in the natural reflex defense of the part, 
owing to the loss of sensation and of trophic influence 
(Chapter XIX.). Primary dilatation of the blood vessels 
must be considered as the result of a paralysis of the vaso- 
constrictor nerves, ascribable to the local injury. The sub- 
sequent slowing of the circulation is in part due to this 
dilatation. 

The vessels of the rabbit's ear are supplied by vasocon- 
strictor fibers, which run in the sympathetic nerve, and vaso- 
dilator fibers, which run in the auricular nerve. Division; 



INFLUENCE OF THE NERVOUS SYSTEM 7 

of the sympathetic nerve leads to great dilatation of the vessels 
of the ear. Division of the auricular nerve usually produces 
no obvious effect, though dilatation of the vessels is observed 
when the peripheral end is stimulated. If all the nerves in 
the rabbit's ear be divided, the vascular changes of inflam- 
mation occur when the ear is dipped into hot water (54 C). 
Indeed, the changes are more rapid than when the nerves 
are not divided. The following experiments, however, show 
that division of one or the other nerve influences the processes 
of inflammation. Thus, if the auricular nerve be divided, and 
the inflammation started by dipping the ear in warm water, 
no hyperemia occurs, but stasis and gangrene of the part may 
ensue. If, on the other hand, the sympathetic alone be divided, 
and the ear be dipped into hot water, well-marked congestion 
is seen, and the inflammation rapidly recovers. These experi- 
ments have been repeated, using the streptococcus of erysipelas 
instead of hot water as the excitant of the inflammation, and 
the results obtained were the same. 

It might be concluded from the first experiment that the 
congestion of the part is mainly due to an active stimulation 
of the vaso-dilator fibers, and it is possible that this is the 
explanation of the phenomenon in a part with such a special- 
ized nerve supply as the ear of the rabbit. In other parts 
of the body, however, in which there is no great evidence 
of the existence of vaso-dilator fibers, it must be concluded 
that the chief means by which congestion of the part occurs 
is by the paralysis of the vaso-constrictor fibers. 

The slowing of the circulation which follows the dilatation 
of the blood vessels and the increase of the blood stream is 
due partly to the dilatation itself, which causes a concentra- 
tion of blood in the part. The adhesiveness of the white cor- 
puscles to the vessel wall may also aid the slowing. The 
presence of blood is not necessary for the phenomenon to occur, 
as stasis is observed if milk or salt solution is substituted for 
blood in the frog. 

Exudation of Liquid. — The amount and character of the 
liquid exuded from the blood vessels depend, to some extent, 



8 INFLAMMATION 

on the nature of the irritant, but also on the looseness of the 
inflamed tissue, and whether inflammation occurs in a serous 
membrane or in a solid tissue. 

The nature of the irritant will be more fully discussed 
when the invasion of the body by bacteria (i. e., the process 
of infection) is considered, but it may here be said that 
although certain irritants usually produce a fibrinous exuda- 
tion, others a clear liquid exudation, and still others a purulent 
exudation, yet one and the same bacterium may, according 
to its degree of virulence, produce either a serous, a fibrinous, 
or a purulent exudation. Thus, the anthrax bacillus, if not 
very virulent, will produce a large serous exudation, when 
injected subcutaneously in an animal. If more virulent, it 
will produce little or no exudation. Another example may 
be taken in the typhoid bacillus, which produces, as the 
result of intraperitoneal injection, liquid exudation without 
the formation of an abscess; whereas, in man and when in- 
jected subcutaneously in the rabbit, it produces an abscess. 
The same may be said of the bacillus coli communis. In 
other cases, again, the exudation is but slight, and the effect 
on the tissues great. 

Composition of Inflammatory Effusions. — Clear effusions, 
such as are obtained from the pleura or pericardium in inflam- 
matory conditions, are all alkaline and of a yellowish or yel- 
lowish-green color, the color being due to the presence of a 
lipochrome. The specific gravity is, on the average, 1018, and 
they clot spontaneously, not only when removed, but often in 
the body cavity. The specific gravity of non-inflammatory 
effusions is 1010 to 1015, and they do not clot spontaneously 
in the body, but a coagulum is produced on adding serum or 
blood, fibrin ferment, or myosinogen. The following table 
illustrates the composition of these fluids. 



EXUDATION OF LIQUID 9 

PERCENTAGE COMPOSITION (IN GRAMS) OF INFLAMMATORY 
AND NON-INFLAMMATORY EXUDATIONS. 





Specific 
Gravity. 


Total 
Proteids. 


Fibrin. 


Serum- 
Albumin. 


Serum 
Globulin. 


Acute Pleurisy 


1020-1023 


35-5 


O.OI6-O. I 


1.24-3 


I.I8-2.I 


Hydrothorax 


IOI2-IOI6 


1.3-2.5 


O.O06-O.OI3 


O.4-O.7 


0.7 1.8 


Subcutaneous (. 
Edema . \ 


IO09-IOI2 


O.3-O.6 


Traces 


O.13-0. 19 


0-4S 


Hydrocele I 
Fluid . . J 


IOI6-I022 


•• 


0.059 


1.35 


3-5 


Pus Serum . 


• • 


6.2-7.7 


• • 




j Lecithin 
\ 0.15-0.056 


Peritoneal 
Fluid \ 

(ascites) . j 


IOIO-IOI8 


2.9-3 5-4 
or 0.6-0.7 


•• 


O.2-2.9 


0.5-2.6 



The proteids consist of fibrinogen, serum globulin, and 
serum albumin; the extractives consist of cholesterin and 
sugar. Inflammatory effusions contain a smaller quantity of 
proteids than blood serum, but a much larger quantity than 
is present in non-inflammatory effusions. The salts are like 
those in the blood. 

Besides these substances, inflammatory effusions frequently 
contain toxic agents, as well as the bacteria producing them. 

The cause of the effusion of liquid is probably the effect 
of the irritant on the endothelial cells of the blood vessels, 
so that increased transudation occurs. The so-called nutrition 
theory (Virchow), which supposed that the increased exuda- 
tion of fluid in inflammation was due to an increased local 
metabolism of the tissues, is not supported by facts, inasmuch 
as inflammation leads to a diminution, and not to an increase, 
of functional activity. 



Diapedesis. — The emigration of white blood corpuscles was 
first observed by Dutrochet in 1824, next by Addison in 
1843, an d subsequently by Waller in 1846; but the most 
systematic study was published by Cohnheim in 1867. He 



io INFLAMMATION 

drew special attention to the ameboid character of the exuded 
leukocytes. 

The diapedesis of the white corpuscle is mainly an active 
process, owing to the ameboid properties of the leukocyte, 
and the direct observation of the process of inflammation in 
the frog's mesentery or tongue demonstrates that the passage 
of the white corpuscle out of the blood vessel is, in the main, 
an active process. Red corpuscles, however, also pass out of 
the blood vessels in the inflamed area, and this movement must 
be a passive one. 

Cohnheim stated that arrest of the circulation of the part 
by compression of the vessel supplying it arrested diapedesis, 
and he did not consider that much, if any, diapedesis occurred 
in the area of stasis. Metchnikoff (and previously Waller), 
however, directly observed the emigration of the white blood 
corpuscle in the area of stasis. The leukocytes show ameboid 
movements both inside and outside the blood vessels, so that, 
at any rate at first, their vitality is not altered by the passage 
through the vessel. Subsequently, however, most of the 
leukocytes die. Some act as phagocytes, engorging not only 
bacteria, but pigment formed from hemoglobin and the debris 
of dead tissue. A very few may develop into the fixed cells 
of connective tissue, during the process of repair. 

The question arises: Why do the leukocytes leave the 
blood vessels at all? Emigration varies enormously in 
extent in different cases of inflammation, and this variation 
is dependent on the nature of the irritant, not only on the 
particular bacterium causing the inflammatory change, but 
on the degree of virulence of the bacterium. The greatest 
amount of emigration is observed in the formation of ab- 
scesses, whether acute or slowly forming. In the case of a 
rapidly acting irritant, such as is produced by virulent bacteria,, 
there is very little emigration; but there may be a great exuda- 
tion of liquid; or, in other cases, there is but little liquid, and 
great necrosis of tissue. With less virulent bacteria more 
emigration occurs. The causes of this variation in the amount 
of emigration as a result of the action of different irritants has 
to be studied. 



EFFECT ON TISSUES n 

Prima facie, there appear to be some irritants which 
conduce to the emigration, and others which diminish it. 
This process of the attraction or repulsion of leukocytes is 
referred to as chemiotaxis, positive and negative (see Phago- 
cytosis, p. 2j). 

Effect of Inflammation on Tissues. — Although the main 
phenomena of inflammation are concerned with the vascular 
system, yet the changes which occur have an effect on the 
tissues in which the inflammation occurs, and these effects 
may be ascribed to two causes. The first is due to the 
deprivation of the part of a proper supply of oxygenated 
blood; the second is due to the direct action of the bacterial 
poisons on the cells of the tissue or organ, associated with 
the condition of pyrexia which is induced in such cases of 
infection. 

i. Effect on Connective Tissue. — The primary effect of 
inflammation is to cause cloudy swelling of the connective 
tissue cells themselves, with some proliferation subsequently. 
Many of the cells degenerate. The fibers of the connective 
tissue swell, and ultimately may undergo hyaline degenera- 
tion. In chronic inflammation there is an increase of the 
connective tissue, mainly of the white fibrous tissue (p. 24). 

2. Cells of Organs. — The primary effect here is to produce 
cloudy swelling of the cells, which may rapidly pass on to 
fatty degeneration, and these changes are observed, not only 
as the result of a local inflammation of the organ, but in 
many cases of general infection, where the effect is due to 
the circulation of poisons throughout the body. Other forms 
of degeneration are also observed, but mainly as the result 
of chronic inflammation, or chronic infection; such, for 
example, as mucoid and dropsical degeneration of the cells. 
The cells which are more particularly observed to be affected 
by cloudy swelling or other changes, as the result of inflam- 
mation or of infection, are the secretory cells, such as those 
of the digestive glands and of the liver and kidney, while sim- 
ilar changes are observed in the heart muscle (Chap. VII. ). 

3. Necrosis. — Necrosis or death of a part, or of the cell 



12 INFLAMMATION 

elements of a part, is one of the main results of the inflam- 
matory, or more correctly speaking, the infective process. 

The degree in which necrosis occurs varies considerably 
in different inflammations, and is due to the nature of the 
irritant. In some but little necrosis occurs; in others, such 
as diphtheria, necrosis is well marked. The varying degrees 
of necrosis sometimes are described as a soft or colliqua- 
tive necrosis, and as a dry, and sometimes fatty, necrosis 
(caseation). 

4. Pigmentation. — Pigmentation may be considered as one 
of the effects of inflammation upon tissues, and results from 
the transformation of the hemoglobin of the exuded red 
blood corpuscles. The final result is the deposit of pig- 
ment both in and between the cells of the permanent tissue 
(Chapter XIV.). 

Varieties of Inflammation. — -Inflammation may be classified 
in two ways. A proper classification would be into divisions 
in which the nature of the irritant would be chiefly considered, 
but there is no advantage in such a division. An anatomical 
classification is more useful. 

Inflammation is either acute or chronic. It may be 
chronic from the first, or a chronic form may follow the 
acute, but in either case it is simply a question of the 
process and degree of infection, and the degree of resistance 
offered by the tissues to the infective process. 

For the present purpose, the varieties of inflammation may 
be classified according to the main feature of the process 
which is present, and this main feature may be one of three 
kinds : first, as regards the predominance of the leukocytic 
emigration; secondly, as regards the character of the liquid 
exudation from the vessels, and thirdly, as regards the effect 
of the inflammation on the tissues. 

1. Predominance of Leukocytic Emigration. — (a) Intersti- 
tial Inflammation (Fig. 6), in which the main feature is a 
leukocytic infiltration in the connective tissue, or between the 
cells of the organ. The inflammatory focus is dry, but little 
liquid being exuded. 



VARIETIES OF INFLAMMATION 



*3 



(b) Purulent Inflammation (Fig. 7) /in which, in addition 
to a large leukocytic emigration, the cells of which degenerate, 
there is exudation of liquid, forming the so-called liquor 
puris or pus serum. 

2. Predominance of Exudation. — (c) Edematous inflamma- 
tion, in which there is a large amount of liquid exudation, 
with a relatively small amount of leukocytic emigration. 




Fig. 6. — Interstitial myositis. 



A transverse section of voluntary muscle under a low power, showing 
the muscle fibers cut transversely. In parts are to be seen radiating lines 
of round cells or leukocytes, showing an early stage of interstitial inflam- 
mation. (For the later stage, see Fig. 77.) 



This form of inflammation occurs only in loose tissues such 
as connective tissue, or in cavities such as the pleura, peri- 
cardium, and peritoneum, or in the lungs, and does not occur 
in solid organs, such as the liver, kidneys, spleen, and heart. 

(d) Croupous or Fibrinous Inflammation (Figs. 8 and 9), in 
which there is but little liquid exudation. The main feature 
is the fibrin which is deposited in the inflamed area. There 
is an emigration of leukocytes, but the predominance of fibrin 



14 



INFLAMMATION 



constitutes a well-mafked variety. This inflammation occurs 
in the skin and the connective tissue, as in some kinds of 
carbuncles; on mucous membranes, as in diphtheria; in lung 
tissue, as in croupous pneumonia, and on the surface of serous 
membranes, pleura, pericardium, and peritoneum. 

3. Predominance of Effect on the Tissues. — (e) Catarrhal 




Fig. 7. — Purulent inflammation. 

Section of a portion of kidney substance under a low power, showing a 
cavity containing a dark mass, composed mostly of pus corpuscles (leuko- 
cytes) in various stages of degeneration, and showing also a leucocytic infil- 
tration of the kidney substance, the interstitial tissue of which is quickly 
increased, widely separating the tubules. These last are indicated in the 
figure only by clear spaces, irregular in shape, the epithelium having in 
great part fallen out of the tissue during the preparation of the specimen. 

inflammation (Fig. 10). In this variety, in which the mucous 
membranes are affected, there are the general signs of inflam- 
mation, such as congestion, leukocyctic emigration, and transu- 
dation of liquid. There are, besides, two changes, the first 
of which is cloudy swelling of the cells of the glands; the 
second, which gives its name to the variety of inflammation, 
is the increased production of mucus by the epithelial cells 
and the cells of the glands. In the acute stages of the 



VARIETIES OF INFLAMMATION 



J 5 



inflammation as well as in some forms of the chronic, there 
is a purulent, as well as a mucoid, discharge from the mucous 
membrane. Catarrhal inflammation may affect any of the 
mucous membranes of the body. 

(/) Ulcerative Inflammation (Fig. n) ; Desquamative In- 
flammation. — Ulcerative inflammation affects the surface of 




Fig. 8. — Croupous inflammation. 

Section of a tonsil, showing false membrane on tne surface. The tonsillar 
tissue is in the lower part of the figure, and is composed of numerous cells, 
which, near the surface, are seen to be loosely attached to the tissue, and to 
be present partly in the false membrane. The false membrane is firmly 
attached to the tonsillar tissue ; it contains a few leukocytes, and shows a 
faint fibrillation, due to the strands of fibrin, but no organized structure. 
At the surface small dark masses are present in the false membrane. These 
are groups of bacteria. (From a case of tonsillar diphtheria in a child.) 



the body or mucous membranes, and consists of the usual 
changes in inflammation, with subsequent death of the super- 
ficial parts, and discharge of the necrosed inflammatory 
area. 

The term desquamative inflammation is practically reserved 
for certain inflammatory conditions of the skin and other 
parts covered by stratified epithelium. Desquamation of this 



j6 inflammation 

epithelium may occur in acute inflammation, as, for example, 
in the gangrenous form, but it is also observed as the result 
of an acute congestion of the skin, after the congestion has 
passed off. This occurs, for example as a sequence of 
several varieties of erythema, and is observed also in scarlet 
fever. It may also occur when there has been no obvious 
previous inflammation of the skin, as in some cases of in- 
fluenza, typhoid fever, and diphtheria. The desquamation. 




Fig. 9. — Croupous inflammation in the lung. 

The figure represents the stage of gray hepatization in croupous pneu- 
monia. The alveoli are shown filled with leukocytes and a few larger cells 
coming from the epithelium, the cells being separated by strands of fibrin. 
The alveolar cells are larger than normal, owing to the distention of the 
capillaries. 

which occurs as the result of inflammation, is, no doubt, 
directly dependent on the diminished nutrition of the epi- 
thelial cells of the skin. 

(g) Gangrenous Inflammation is applied to cases in which 
there is extensive destruction of the tissues of the inflamed 
part. It is due to particular forms of bacterial infection, and 
is sometimes associated with thrombosis of the vessels. 

(h) Parenchymatous Inflammation. — The term parenchy- 
matous inflammation is a misnomer, inasmuch as inflam- 



VARIETIES OE INFLAMMATION 



*7 



niatory changes have to do with an alteration in the circula- 
tion of the blood, and not primarily with any change in the 
parenchyma or proper tissue of the organ; that is, the cells 
of the liver, kidney, or connective tissue do not, of them- 
selves, undergo inflammation, without the vascular changes 
occurring^. 




Fig. io. — Catarrhal inflammation. 

The figure shows a transverse section of a small bronchus in a patch of 
broncho-pneumonia. The epithelium of the bronchial mucous membrane 
has proliferated, and some of it has disappeared, leaving the mucous mem- 
brane irregular on the surface. Around the bronchus there is great thick- 
ening of the tissue, due mainly to leukocytic infiltration. The alveoli are for 
the most part obliterated, and there is great dilatation of the blood vessels. 



The term parenchymatous inflammation is sometimes made 
interchangeable with interstitial inflammation. This, however, 
is a mistake. The only parenchymatous change which can 
properly come under this heading is one which affects the 
cells of the solid organs in the course of certain infections, 
namely, the cloudy swelling of the heart, liver, and kidney, 



1 8 INFLAMMATION 

the changes in parenchymatous nephritis, as well as, perhaps, 
a similar change going on to fatty degeneration, which 
occurs in phosphorus and some other forms of poisoning. 

(i) Chronic Proliferative Inflammation (Figs. 12 and 13.) — 
This is observed mainly in the skin, and parts of the body 
covered by stratified epithelium : it also occurs in glands. 




Fig. 11. — Ulcerative inflammation. 

The figure shows a transverse section of an ulcerating solitary- 
follicle in the large intestine. The mucous membrane is thickened by a 
leukocytic infiltration. The glands are degenerated, and remains of 
them are seen on the base of the ulcer, which is mainly occupied by the 
inflamed follicle. The submucous coat, the muscular coat, and peritoneal 
coat are all thickened, mainly by the leukocytic infiltration. 



The inflammatory process is usually chronic and leads to a 
great proliferation and heaping up of the epithelium, some- 
times in the form of warts. Examples of this form of 
inflammation are observed in the skin, as in gonorrheal 
warts which may show, on section, no deep suppurating foci, 
and in post-mortem warts (verruca necrogenica) , which are the 
result of post-mortem wounds, and show chronic inflamma- 



NATURE OF THE IRRITANT 



19 



tion with foci of suppuration and great proliferation of the 
skin and epithelium. This same variety of inflammation is 
also seen as the result of syphilis either in the skin, nose, or 
buccal cavity. It also occurs in the esophagus in some cases 
of dilatation very chronic in duration, and, as a rule, not due 







Fig. 12. — Proliferative inflammation. 

The figure shows a transverse section of the mamma, in which the 
acini are irregular in shape, and in which the epithelial cells are greatly 
proliferated. There is an increase of fibrous tissue between the acini, 
and there is a tendency to cyst formation in the affected acini. 



to obstruction at the cardia. 
flammation of the mamma. 



It is observed in chronic in- 



Nature of the Irritant. — Many different kinds of agents 
will produce the changes observed in inflammation. Bacteria 
and their products are. in disease, the main agents in pro- 
ducing inflammation. Other irritants will produce a local 



20 INFLAMMATION 

inflammation which subsides, but the result of the action of 
bacteria is to produce a progressive inflammation. When this 
increases up a certain point it ends in death of the part 
or resolution. 

Irritant poisons, such as croton oil, turpentine, and 
corrosive sublimate, as well as mineral acids, will produce 
the changes observed in inflammation, but the action is not 
progressive. 

The Course of Inflammation. — i. Resolution and Repair. — 
A slight inflammation, in which there are well-marked vascular 




Fir. 13. — Chronic proliferative inflammation. 

The figure shows a vertical section of a gonorrheal wart. At the 
surface is seen thickening of the horny layer of the epithelium, which 
above is structureless, and below is composed of flattened cells. Be- 
neath this layer is a greatly proliferated Malpighian layer, forming the 
greater part of the wart. The epithelium is arranged in a digitate man- 
ner, the body of the finger, or the core of the wart, being composed of 
connective tissue, in which are a few blood vessels. 



changes, and in which there is no formation of pus or destruc- 
tion of much of the proper tissue of the part, may be recovered 
from, resolution taking place. The congestion diminishes; 
the blood current is restored; the exuded liquid is absorbed; 
the leukocytes usually dying, and the debris being carried away 
by the phagocytes. Such a slight degree of inflammation may 
be recovered from without any permanent damage to the 
tissue. 

In more severe cases, however, damage is done to the 



RESOLUTION AND REPAIR 



21 



tissue, and repair takes place. The process of repair has 
to be considered in the following circumstances : whether 
epithelium, columnar or stratified, has been destroyed, so that 
there is an erosion or ulcer; whether there has been more or 
less extensive destruction of the cells of an organ : whether 
the inflammation has occurred on the surface of a serous 
membrane, and lastly, whether there has been great destruc- 




Fig. 14. — Granulation tissue. 

The tissue is composed mainly of small round cells, chiefly leukocytes, 
with other elongated cells not well shown in the figure, owing to the low 
power of magnification. At two parts of the figure can be seen areas which 
contain nuclei in an apparently amorphous mass. These areas are masses 
of epithelial cells of the skin which are undergoing degeneration. (The 
specimen was taken from a wound of the skin.) 

tion of tissue by abscess formation or by the occurrence of 
gangrene. Wherever there is an ulcer or great destruc- 
tion of the tissue, or where the inflammation occurs on 
the surface of a serous membrane, granulation tissue is 
formed. 



Granulation tissue (Fig. 14) is composed of cells among 
which numerous blood vessels ramifv and anastomose. The 



22 INFLAMMATION 

cells are, in part, leukocytes, but also consist of elements 
derived from the fixed cells of the part. These elongate, 
forming the so-called fibroblasts, which ultimately develop into 
connective tissue, the tissue of the scar. The vessels are at 
first mere channels in the tissue. They subsequently become 
lined with endothelium and are connected with the surround- 




Fig. 15. — A healing wound. 

This figure shows groups of epithelial cells beneath the epithelium of the 
skin, which is covering the wound. The groups of cells are separated by- 
tissue, which contains a large number of leukocytes (granulation tissue). 
The epithelial cells are seen in all stages of division. They are the normal 
epithelial cells which grow from the edge of the wound in the process of 
healing, and are covered by the epithelium growing above them, mixing 
with the granulation tissue below. Eventually they disappear. 

ing vessels. Most of the cells of the granulation tissue 
ultimately disappear; the remainder aid in forming connective 
tissue, and some remain as permanent connective tissue 
corpuscles. 

Repair of epithelium takes place by means of the sub- 
division of the epithelial cells at the periphery of the lesion 
(Fig. 15). Epithelial cells can only develop from similar cells. 
The same is true of cells of organs and of muscle fiber, and 



REPAIR 23 

in any case in which there is a great amount of destruction 
of the heart muscle, the liver, kidney, or other cellular organs, 
no reproduction of the cell structure takes place, a connec- 
tive tissue scar alone resulting. Such damage to the cell as 
cloudy swelling and slight fatty changes may be recovered 
from. 

In cases where there is inflammation of the liver and 
kidney, subdivision of the cells is observed in parts. This 
subdivision, however, is hardly to be considered an attempt 
at repair, but is more correctly described as a result of 
irritation, similar to the subdivision of the endothelium of 
the blood vessels which sometimes occurs in an inflamed 
area. 

Where there is a solution of continuity of tissue by means 
of a knife or other cause of wound, the process of repair 
differs according as to whether the wound is infected by a 
bacterium or not, whether the edges of the wound are apposed 
or not, and thirdly, whether the wound itself has caused much 
destruction of tissue. 

The process of repair in infected wounds need not be 
specially considered, as repair takes place by granulation 
tissue. In non-infected or aseptic wounds, repair differs ac- 
cording to whether the edges of the wound are clean cut and 
apposed, or whether there is much destruction of tissue and 
bruising. In clean-cut, aseptic wounds, with edges apposed. 
the healing is by primary union. In these the amount of 
tissue killed by the action of the knife is but small. Leukocytes 
emigrate from the blood vessels to the edges of the wound, 
some liquid is excluded, and healing takes place by means of 
the division of the cells of the part, the leukocytes being mainly 
employed in removing the dead tissue and the small amount of 
exuded blood. 

When there is much destruction of tissue, as well as effusion 
of blood into the part, more evident granulation tissue is 
formed than in the first case, leukocytes act as phagocytes, re- 
moving the dead tissue and the effused blood; repair takes 
place by the granulation tissue in the manner previously de- 
scribed. A similar process takes place if the edges of the 



24 INFLAMMATION 

wound gape, and still remain aseptic, the epithelium spread- 
ing from the edges of the wound. 

2. Chronic Inflammation. — The term chronic inflammation 
is sometimes employed in two different senses. In true chronic 
inflammation the process is progressive, although slow. This 
means that the infective agent is still acting as an irritant. 
But the term is also applied to conditions in which there has 
been a profound change in an organ or part, caused by a pre- 
vious inflammation in which there was destruction of cells 
with the formation of fibrous tissue. A typical chronic in- 
flammatory process occurs in a chronic abscess, especially in 
those forms which occur in the skin and in which there are 
multiple foci of suppuration, as well as in the lesions of tuber- 
culosis, syphilis, and leprosy. 

With regard to internal organs, however, chronic inflam- 
mation shows itself in three different forms, which may all be 
associated with a small-celled, interstitial infiltration, an in- 
crease of fibrous tissue (fibroid hyperplasia) and degeneration 
of the cells of the organ. Thus, in the kidney, in chronic inter- 
sitial nephritis, both small-celled infiltration and fibrosis are 
observed, and in many cases these are associated with a fatty 
degeneration of the cells of the tubules. In the stomach, in 
chronic inflammation, the interstitial fibrosis may be slight, 
while the degeneration of the cells of the glands is great. In 
the liver, fibrosis is, as a rule, predominant, the degeneration of 
the cells being secondary (Chapter VII.). 

Inflammation of Non-vascular Tissues and in Invertebrata. 
— In Non-vascular Tissues of Warm-blooded Animals. — The 
changes which result from the injury of non-vascular tissue 
depend on the strength of the irritant and the duration of 
exposure to the irritant, and are according to the degree of 
injury. Experiments were performed by Senftleben on the 
cornea, the irritant used being a solution of zinc chlorid (66 
per cent. ) , with a little chlorid of sodium added. This caustic 
solution was applied to the center of a rabbit's cornea for a 
greater or less length of time. Results varied in the two fol- 
lowing ways (Figs. 16 and 17). If the caustic solution 



OF NON-VASCULAR TISSUES 



25 



was applied for so short a time that there was no solution of 
continuity of the corneal surface, a certain number of cells 
were killed by the caustic and a slight opacity of the cornea 
resulted. Repair took place by means of division of the corneal 
corpuscles, which lie, with their branched processes, between 
the layers of corneal tissue. The daughter cells passed 
from the healthy tissue to the injured; the dead cells were 




Fig. 16. — Repair of non-vascular tissue. 

The figure is a drawing, under a high power, of a horizontal section 
through a lesion of the cornea made by the application of chlorid of 
zinc, no solution of continuity occurring. The corneal corpuscles are 
seen, b and c represent those which have been killed by the caustic ; a 
represents the normal corneal corpuscles, which are seen to send pro- 
jections into the damaged area, these projections being nucleated, and 
eventually replacing the damaged cells. (Senftleben.) 

partly removed by means of these new cells, which eventually 
developed into adult corneal corpuscles (Fig. 16). As the re- 
sult of this injury, there was no leukocytic infiltration, and no 
congestion of the vessels of the conjunctiva at the periphery of 
the cornea. 

If, however, the injury to the center of the cornea were such 
as to produce a solution of continuity (Fig. 17), in addition to 
the changes above mentioned, there ensued deep congestion 



26 



INFLAMMATION 



of the vessels of the conjunctiva, and emigration of leukocytes, 
which traveled from the periphery towards the central part 
which was injured. It is probable that, in this case, some of 
the caustic solution was absorbed by the cornea, and traveled 
in the corneal spaces to the conjunctiva, where it produced 
inflammatorv effects. There could be no reflex nervous 



s, 




Fig. 17. — Inflammation of non- vascular tissue. 

The figure represents a horizontal section, under alow power, 
of the cornea, which has been damaged by the application of 
chlorid of zinc ; a solution of continuity has occurred (c). Out- 
side this is seen (d) a collection of dots, which represent leuko- 
cytes. Then comes a clear zone, in which the circles represent 
corneal corpuscles, most of which have been destroyed by the 
caustic. Then comes a third zone of leukocytes, and, finally a 
zone (a) of normal corneal corpuscles. (Sentftleben.) 

mechanism concerned in such a case as this. The repair of 
the solution of continuity takes place by means of non-vas- 
cular granulation tissue, and if complete healing takes place, 
the leukocytes disappear for the most part. Some of these, 
however, may be transformed into corneal corpuscles, but 
most of the latter are reproduced from pre-existing corpuscles. 
In bacterial inflammation of non-vascular tissues similar phe- 
nomena are observed, but the process is intensified, so that the 



PHAGOCYTOSIS 27 

leukocytes are distributed throughout the whole of the tissue 
(Fig. 18). 

Inflammation in Invcrtcbrata. — Phagocytosis. — The expla- 
nation of the emigration of white blood corpuscles in the pro- 
cess of inflammation in vertebrate animals has to a great extent 
been made clear by the resarches of Metchnikoff into phagocy- 
tosis, and into the changes which occur in invertebrate animals 
in response to a mechani- 
cal injury or the invasion 
of micro-organisms. 




Phagocytosis may be de- 
fined as the process by 

which animal cells take in Fjg . 18.— Inflammation of non-vascular 
solid particles, living or tissue. 

dead, SOme beinSf digested, The figure shows part of a vertical section 

11 of the cornea, which is inflamed (bacterial 

Others discharged. Others corneitis), and is in reality an exaggeration or 

. ° advanced stage of Fig. 17. The surface of the 

agram. if living, Capable Of cornea is irregular from the destruction of 

1 11 rr^i • the epithelium, and beneath this layer is one 

deStrOVing the Cell. llllS of leukocytes, which are also scattered irreg- 

, ularlv through the corneal tissue. 

is a process that is very ex- 
tensively observed in the animal kingdom, and may be dis- 
cussed under the heading of physiological and pathological 
phagocytosis. 

Physiological phagocytosis is observed in many of the 
lower animals, in which it is one of the means of obtaining 
and digesting food. The ameba takes in bacteria and 
diatoms from the water in which it lives, digesting some of 
these, rejecting others. Some of the living organisms taken 
in by the ameba may actually increase within its body, causing 
the death of the cell. In such a case as this there is no sharp 
line between physiological and pathological phagocytosis. 
The hydra, which is a simple double cellular organism with 
an elementary digestive cavity, by means of the cells lining 
in this cavity takes its food in the form of solid particles. A 
uni-cellular organism, like Paramecium, also receives its food 
in this manner. 



28 INFLAMMATION 

Amongst warm-blooded animals the process of absorption 
of fat in the small intestine is an example of physiological 
phagocytosis. The minute globules of fat are taken up by 
the epithelial cells, and then by the leukocytes, by which 
they are conveyed to the lymph stream. The absorption of 
bone during ossification, by which the secondary areolae are 
formed, is another example of the physiological process, as 
well as the absorption of bone in old age by means of the 
osteoclasts. The absorption of the branchiae in the tadpole 
during its transformation into a terrestrial animal is also an 
example of phagocytosis. 

Pathological phagocytosis is observed when a living 
organism is injured mechanically, infested by a parasite, or 
when an inert foreign body is introduced into its substance. 
In many cases it is a battle between the host and the 
parasite, in which, in some cases the host, in others the 
parasite, gains the upper hand. The parasite itself may 
produce an injurious effect on the host in two ways: either 
( i ) mechanically, by its mere increase destroying the vitality 
of the tissue or of the host, if this be a lowly formed animal 
or if the parasite destroy a vital organ; or (2) by its secre- 
tion of toxic substances, which destroy the vitality of the 
host. In the latter case the action of the parasite is usually 
much more deleterious. 

Metchnikoff has described the following chain of events 
as occurring in lowly organized animals, either as the result 
of injury or parasitism : with the uni-cellular organisms, 
such as the ameba, some of the living particles taken in 
serve, as has been stated, as food. Others again, instead of 
being digested or rejected, may produce a fatal disease. 
Metchnikoff has observed such a disease in the ameba, 
which takes into its substance a microsphera, an organism 
composed of nucleated round cells multiplying by division 
(Figs. 19 and 20). This organism may multiply to such an 
extent as to kill the ameba. In other instances, in uni- \ 
cellular organisms, the parasite taken in may, after a short 
period of life and subdivision, be killed and digested by its 
host. There is evidence, then, even in these lowly organ- 



PHAGOCYTOSIS 



29 




isms, of a struggle for existence between the parasite and 

its host. 

In multi-cellular organisms, 

phagocytosis becomes more 

complicated, owing to the 

progressive differentiation of 

function in the cells. These 

organisms are composed of 

three layers, ectoderm, endo- 

derm. and mesoderm, and it 

is to the cells composing the 

last of these that the property 

of phagocytosis becomes even- 
tually mainly limited in the 

progress of evolution. The 

sponges protect themselves 

against harmful bodies by 

means of their contractile ecto- 
derm cells, but the cells of the 

mesoderm and endoderm also 

act as phagocytes. By thrust- 
ing a small tube of glass into the body of spongilla, Metchni- 

koff observed that the 
tube became surrounded by 
mesoderm cells, which 
eventually fused together, 
forming a primitive giant 
cell (Figs. 21 and 22). 

In the simple animals 
which possess no mesoderm 
^.SSpMc' (celenterata), the endo- 
derm cells, and sometimes 
the ectoderm cells, play the 
role of phagocytes; but in 
all animals which possess a 
mesoderm, it is the cells of 
this layer which are mainly 
the phagocytes. They sur- 



Fig 19. — Phagocytosis. 

Drawing of an ameba, showing com- 
mencing invasion by the microsphera. In 
the lower part of the figure diatoms are 
seen in the substance of the ameba. These 
are subsequently digested and utilized as 
food. Above this is a vacuole, and at 
a are seen the spores of the microsphera. 
The later stage is shown in Fig. 20. 
(Metchnikoff.) 




^mssmm. 



Fig. 20. — Phagocytosis. 

This shows the advanced stage of the in- 
vasion of the ameba by the microsphera. 
The animalcule is now becoming quiescent, 
slowly dying from the great growth and di- 
vision of the invading micro-organisms. 
These are shown scattered throughout the 
protoplasm as spherical bodies. (Metchnikoff.) 



3° 



INFLAMMATION 



round and attack harmful substances introduced into the 
body of the animal, and frequently fuse together, forming 
plasmodes or giant cells. This has been observed in the 
medusae, echinoderms, worms, and vertebrates. The meso- 
derm cells, which are at first a more or less fixed layer of 
the embryo, eventually in part become the wandering cells of 
the body, and are present in the fluid which fills the body 

cavities of the lower animals and 
the vascular system of such ani- 
mals as molluscs and arthropoda. 
When such an animal is injured, 
there is an accumulation of these 
cells at the injured spot, just as 
in the inflamed area in a warm- 
blooded animal. A similar accu- 
mulation occurs if an inert foreign 
body, such as a piece of glass or 
a little pigment, is introduced into 
the tissue of the animal. When 
the foreign body is a living agent, 
there is evidenced the struggle 
between the host and the parasite 
or infective agent, and one ex- 
ample of this, which was well 
worked out by Metchnikoff, was 
that occurring in the water flea 
(Daphnia magna), which was 
found infested in a pond with a 
kind of yeast called Monospora 
bicuspidata. It was found that, at 
certain periods, an epidemic of this disease would kill off nearly 
all the daphnise in the pond, whereas, at other periods the 
animal would survive, although it might contain a few para- 
sites. The ripe spores of the fungus are eaten by the 
animal, and pass through the intestinal wall into the body 
cavity. The germinating spores here become surrounded 
by the leukocytes, and one of two events may happen : 
the spores may rapidly develop, and the parasite increase 




Fig. 21. — Phagocytes. 

B shows a plasmode or giant 
cell, which has been formed by fu- 
sion of phagocytes in the body cav- 
ity of a worm, around a foreign 
substance. A shows a single pha- 
gocyte vacuolated in parts, and with 
numerous projections or pseudo- 
pods. (Metchnikoff.) 



PHAGOCYTOSIS 31 

so as to fill the body cavity and eventually destroy the life 
of the animal, or, becoming surrounded by leukocytes, they 
become degenerated and die, the animal gaining the upper 
hand. 

If the non-vascular fin of young tadpoles of the lower 
amphibia (urodeles) be slightly injured, the ameboid cells 
collect at the injured spot, the fixed cells of the tissue taking 
no part in the process. In older tadpoles, when the blood 
vessels have developed, there is still this accumulation of 
leukocytes at the injured spot; but, in addition, there are the 




Fig. 22. — Phagocytosis. 

This figure shows the effect of passing a spicule of glass into the 
body of a sponge (spongilla). The wandering cells of the body cavity- 
are attracted by the foreign body, which is seen at one part to be becom- 
ing surrounded by the cells. The figure illustrates the point that inert 
matter attracts the phagocytes. (Metchnikoff.) 

phenomena of inflammation, such as the acceleration of the 
blood stream and the other changes which are observed in 
the higher animals. 

As Metchnikoff points out, the attraction of leukocytes to 
the injured spot must, in the process of the evolution of in- 
flammation, be considered the primary; the vascular changes 
being, so to speak, added. 

In the higher animals phagocytosis is a part of inflamma- 
tory and of infective processes. Inasmuch as nearly all the 
inflammatory processes are part of infection, phagocytosis is 
really mainly associated with the invasion of the body by 
micro-organisms. The cells which act as phagocytes in the 



32 INFLAMMATION 

higher animals are chiefly the wandering mesoderm cells 
(the leukocytes), and some of the elements of the splenic 
pulp. The endothelial cells of the blood vessels also act 
as phagocytes. In leprosy they frequently contain the 
bacillus : tubercle bacilli, injected into the circulation, are 
taken up by the endothelial cells of the vessels, and a 
similar result has been observed with the bacillus of swine 
erysipelas. 

Varieties of Phagocytic Leukocytes. — There are four chief 
varieties of leukocytes found in the blood, and two other 
smaller varieties : only two are actively phagocytic. 

The Mononuclear Leukocyte (Fig. 94) is also called the 
large lymphocyte, hyaline cell, and macrophage or macro- 
phagocyte. It forms only 2 to 8 per cent, of the leukocytes 
of the blood. It has a single round or kidney-shaped nucleus, 
and a large amount of hyaline protoplasm without granules. 
The protoplasm stains well. It differs from the lymphocyte 
by being actively ameboid and phagocytic. 

Polymorphonuclear Neutrophil Leukocyte (Fig. 94) — 
(finely granular oxyphile, microphage). This leukocyte 
forms the largest proportion of those in the blood, from 60 to 
70 per cent. : in children the proportion is lower, 18 to 40 
per cent. They are absent from celomic fluid, and are the 
usual form of pus cell. They, indeed, are the chief leuko- 
cytes which emigrate from the blood vessels in inflamma- 
tion. When stained by aniline dyes their appearance is very 
characteristic. When deeply stained with eosin and methy- 
lene blue or with Ehrlich-Biondi, the nucleus is branched, the 
protoplasm itself fairly abundant, showing numerous small 
granules, which stain feebly with acid dyes (eosin and fuch- 
sin). These leukocytes are the chief phagocytes, and are 
actively ameboid. 

The consideration of the other leukocytes will be reserved 
for the discussion of the blood (Chapter XL). For the pres- 
ent purpose it may be noted that the chief phagocyte is the 
polymorphonuclear neutrophile and the other phagocyte is 
the hyaline cell or the large lymphocyte. 



PHAGOCYTOSIS 33 

The phenomenon of phagocytosis is frequently observed 
in infective processes occurring in disease, in the localities 
in which the infective agent grows. The leukocytes are 
observed to contain bacteria within their substance, but these 
are also present, and are growing, in between the cells. In 
some cases there is abundant phagocytosis; in others but 
little. In some instances the bacteria reside chiefly in 
the cells. This is true of the leprosy bacillus and of the 
gonococcus, the former of which is an example of a very 
chronic infection, the latter of an acute. In pus infection 
phagocytosis may or may not be abundant, but in some other 
infections phagocytosis is practically absent, such, for example, 
as the infection by virulent anthrax and other rapidly acting 
micro-organisms. 

From what has previously been said regarding the reaction 
between living cells and foreign bodies or infective agents 
brought into contact with them, the degree of phagocytosis in 
any particular lesion cannot be considered a haphazard occur- 
rence. Experiment has shown that foreign substances in 
some cases attract the living cells, in other cases repel them. 
This action is referred to as chemiotaxis or trophotropism ; 
positive when the leukocytes are attracted, negative when 
they are repelled. 

A good example of this action is seen in one of the lower 
fungi (Ethalium septicum), one of the myxomycetes, a 
gelatinous mass which grows in tanning vats. This fungus 
was found to be attracted by oak infusion, and repelled by 
a solution of glucose. 

Of substances which induce positive chemiotaxis, the fol- 
lowing may be enumerated : 

Most bacteria living or dead, also substances extracted from 
the bodies of bacteria and called proteins (Buchner), papain, 
leucin, and copper and mercury compounds. 

Of substances which induce a negative chemiotaxis, the 
following are the chief : 

Virulent bacteria, alcohol, chloroform, glycerin, bile, 
quinin, abrus, strong solutions of sodium and potassium salts, 
and salts of gold, silver, and iron. 



34 INFLAMMATION 

The attraction and repulsion of the living cell no doubt 
depends on the nutritive relation, mainly chemical, between 
the foreign substances and the cell, an idea which will be 
further developed in the consideration of the subject of im- 
munity (Chapter VI.). 



CHAPTER II 

CHANGES IN THE BODY TEMPERATURE IN DISEASE; 
PYREXIA 

The Normal Body Temperature and its Maintenance. — In 
health, the temperature of the body shows diurnal variations 
between certain limits, which are not exceeded, whatever the 
exercise or food taken. The highest temperature of the mouth 
during the day is a little under 99° F. ; the lowest tempera- 
ture occurs at midnight, or soon after, and varies between 
96° and 97° F. This type is reversed if sleep is taken during 
the day and the individual works at night. A temperature 
above 99.5° F. in the mouth is an abnormal condition; that is, 
it is a febrile state. 

The axillary temperature is about 0.5° F. less than that of 
the mouth and the rectal temperature varies in the day from 
98.2° to 100.4 F. 

Under the age of twenty-five years the daily variation of 
the temperature is about 2° F. ; over the age of forty the 
daily excursion is about I°R; and in old age the daily 
excursion may be greater than this and more variable. 
The daily excursion is greater when manual labor is per- 
formed. 

The normal type of temperature may therefore be described 
as follows (Fig. 23) : 

Starting at twelve midnight, when the temperature is 
lowest, namely, 96° to 97° F., there is a gradual rise in the 
early hours of morning until after breakfast. A cold bath in 

35 



36 CHANGES IN THE BODY TEMPERATURE IN DISEASE 

the morning before breakfast causes, in some cases, a rise in 
the mouth temperature. From the morning meal till mid- 
day, or later, the temperature is maintained between 98° and 
99° F. There is then a gradual fall till midnight, if no further 
heavy meal is taken. If, however, a large meal is taken in 
the evening, the temperature again rises somewhat, and tends 
to fall to the lowest normal after midnight. 



F 


700 



98 



97 



96 



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! V "• " •• f ■■'.;■■■■ 



Fig. 23. — Chart of the mouth temperature, taken hourly, of a 
healthy lad aged twelve years (Ringer). 



The body temperature between the normal limits is main- 
tained by a balance between heat production in the body 
(thermogenesis) and heat loss from the body (thermolysis), 
a balance which is regulated by the nervous mechanism 
(thermotaxis). There is a constant and varying production 
of heat in the body by the activity of the cells of the 
tissues, the sources of energy and heat being mainly the 
carbohydrates and fats taken in with the food, and utilized 
by the protoplasm of the cells. Muscular activity leads to 
great production of heat, the muscles forming one-half of the 
body; but even during rest heat is provided by muscular 
metabolism. Gland activity also produces heat, the greatest 
source of heat from this cause being the liver. The hepatic 
blood is the hottest in the body, being 104° F. The blood in 
the aorta is 102 F., the mean temperature of the blood being 
102. 2 F. (39°C). 

There is a constant loss of heat from the body by way 



TYPES OF PYREXIA 37 

of the skin, the lungs, and the kidneys; from the skin by 
means of radiation of heat and the evaporation of the sweat; 
from the lungs by means of the warming of the inspired air 
and the evaporation of the water in the expired air. In 
the kidneys the loss is due to the passage of the warm 
urine. 

In health extra exertion does not lead to a rise of body 
temperature, nor does excessive loss of heat lead to a fall. 
The reason for this is that heat production, and, to a greater 
extent, heat loss, are regulated by a nervous mechanism, which 
is essentially a reflex one. 

The central heat centers are closely connected with the 
vaso-motor, secretory, sensory, and thermic nerve fibers in 
the skin. " Heat " centers have been described in several 
parts of the cerebral hemispheres. Thus, in the motor area 
of the cortex, destruction on one side causes an increased 
temperature in the extremities of the opposite side lasting 
for a considerable time after the injury. Stimulation of the 
centers causes a slight temporary cooling. Basal " heat " 
centers have also been described; on the median side of the 
corpus striatum, between the corpus striatum and optic 
thalamus, and at the anterior end of the optic thalamus; 
destruction of these parts by means of a needle causes a rise 
of body temperature. The rise of temperature in injuries 
to the human brain confirms the existence of the influence of 
the central nervous system on the body temperature. The 
reflex nervous mechanism is chiefly stimulated by cold and 
heat. 

Variations of the Body Temperature in Disease. — Pyrexia. 
— Variations in the normal daily excursion of the temperature 
occur in two different directions. The temperature may 
be continuously subnormal, as in the first period after the 
fall of the temperature in certain infective diseases, and in 
certain chronic diseases associated with profound changes 
in metabolism ( diabetes, renal disease, neurasthenia). A 
temperature of 98.4° F. is artificially taken as the normal. 
A temperature of 99.5° F. is considered as the limit at 
which pyrexia begins, and the following table shows the 



3 8 CHANGES IN THE BODY TEMPERATURE IN DISEASE 

terms in common use for differentiating the degree of body 
temperature : 



95° F. 
96. 8° F. ) 
97-7° F. f • 
98.4 F. 


. Collapse. 
. Subnormal. 
. Normal. 


102.2° F. ) 
103 F. \ 
104° F. ) 
105 F. \ 


. Moderate pyrexia. 
. High pyrexia. 


99-5° F. ) 




105.8° F. { 




100. 4 F. (. . 


Slight pyrexia. 


and (. 


. Hyperpyrexia. 


101.5° F. \ 




above \ 





Types of Pyrexia. — These are usually divided into contin- 
uous and remittent, intermittent and hectic. 

The continuous type (Fig. 24) is when during the course, 
the temperature in its remissions never falls to the normal, 
but is regulated to a higher normal, the daily fluctuations 
being i° to 2 F. In the remittent type, the daily fluctua- 
tions are more than 2 F., and may be 4 or 5 F., but the 
temperature never falls to the normal. In the intermittent 
and hectic type (Fig. 25) the temperature falls to the normal 
or subnormal each day, and this may either be in the morning, 
as is usual ; or at night, giving, in the latter case, what is called 
the typus inversus. The daily fluctuations may be 6° or more. 

These types of pyrexia must be distinguished from the 
pyrexia of a disease. Some diseases show, in their course, a 
regular type, others an irregular (Fig. 26). The pyrexia of a 
disease may end suddenly, as by crisis, the temperature falling 
to the normal, or below, within five to twenty-four or thirty- 
six hours (Fig. 27) ; or slowly, as by lysis, the temperature 
showing a gradual or " step-ladder" fall to the normal or below, 
this fall occupying a period of three or more days (Fig. 24). 

In hyperpyexia^ (Fig. 28), which occurs in typhoid fever, 
rheumatic fever, diphtheria, the exanthemata, and in some 
cases of disease and injury of the central nervous system, the 
rise of temperature is sometimes sudden and sometimes 
gradual. 

Symptoms and Pathological Changes in the Pyrexia! State. — 
The circulation is affected as shown by an increased frequency 
of the cardiac beat; the respiration shows an increase in 



METABOLISM IN PYREXIA 



39 



the number of respirations per minute; and there is a diminu 
tion in the secretion of saliva, gas- „ 

. • o e> co r^ 

trie juice, pancreatic juice, urine, 
sweat, and bile. Nutrition is im- 
paired; and the effect on the 
nervous system is well marked, 
as shown by the rigor, headache, 
muscular weakness, and, in acute 
pyrexial diseases, by a state of ex- 
citation which may proceed to 
delirium and end in coma. 

The symptoms show great 
variations in individual pyrexial 
diseases. In some there is no 
greatly increased frequency of the 
cardiac beat, nor is the respiration 
markedly affected. In others, the 
dry skin is not observed, and pro- 
fuse sweating occurs, while the 
symptoms associated with the 
nervous system show considerable 
variation. It is difficult, if not 
impossible, to say how far these 
symptoms are due to the state of 
pyrexia and how far to the action 
of the specific poisons which are 
circulating in the body in infective 
disease. 

In the pyrexial state there is 
evidence of increased metabolism, 
as shown by the increased dis- 
charge of carbonic acid ( CO.,) , and 
increased excretion of urea. 

1. Respiratory Exchange. — 
There is an increased activity, 
leading to an increased intake 
of oxygen. The respiratory quotient is the proportion 
between the output of carbonic acid and the intake of oxygen 







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METABOLISM IN PYREXIA 



43 



q • • The respiratory quotient in fever may be unaltered or 
diminished; it has been found very variable in the different 




wo 



Fig. 28. — Hyperpyrexia in a case of typhoid fever. 

experiments performed. Liebermeister found the respiratory 
exchange doubled or trebled, two or three times the normal 
amount of CO, being discharged. In his experiments, Reynaud 
found that the increased intake of oxveren was more than the 



44 CHANGES IN THE BODY TEMPERATURE IN DISEASE 

output of carbonic acid, thus diminishing the respiratory 
quotient. 

2. Nitrogenous Metabolism: Dichargc of Nitrogen. — 
There is an increased discharge of urea, which was described by 
Traube in 1855. ^ n J ^59 Ringer investigated a case of 
malaria, and showed that the increased discharge of urea 
began before the onset of the rigor; it diminished rapidly 
after the onset of the pyrexia. This is due to the retention 
of urea in the body; since, with the crisis, there is a greatly 
increased discharge, which is sometimes called the epicritical 
increase, and is simply caused by the removal of the retained 
urea. The increased excretion of urea means an increased 
destruction of tissue proteid, and this destruction in pyrexia 
is sometimes more than doubled, compared to the normal. 
The nitrogen discharge diminishes as the pyrexia continues 
and shows diurnal variations. Not only is the amount of 
urea discharge increased, but also that of ammonia salts, of 
creatinin, of hippuric acid, and of uric acid. The pyrexial 
patient lives on his fat and proteid, owing to the diminished 
quantity of food taken. The available fat is soon exhausted, 
and the proteid then disintegrates. In lean but muscular men 
with high pyrexia there is at first a very great increase in the 
urea discharge. 

Other evidence of the disintegration of tissue proteid is 
obtained from the urine. Thus the amount of acetone, which 
normally only exists in the urine to the amount of 0.0 1 gram 
in the twenty-four hours, is increased ten to forty times, the 
increase usually disappearing with the pyrexia. Two other 
bodies not normally present may take their appearance, accto- 
acetic acid and fi- oxybutyria acid. The former is not constantly 
found : it is observed in some cases of chronic lung tubercu- 
losis, as well as in certain non-febrile diseases, such as inani- 
tion, diabetes, cancer, poisoning, and gastro-enteritis (Chap- 
ter XVIII. ). The latter acid is found mainly in scarlet fever, 
measles, and typhoid fever. In pyrexia^ volatile fatty acids 
(formic, acetic, butyric, and propionic), are sometimes found 
in the urine: occasionally lactic acid is present. 

It has been shown that the administration of sugar in 



URINE IN PYREXIA 45 

the febrile state diminishes the amount of urea discharged. 
The subject, however, cannot be considered simply from the 
point of view of metabolism. Thus, the increased disintegra- 
tion of proteids is shown by the increased discharge of urea, 
and is not explained completely by the exhaustion of the fat, 
as it still occurs when a large amount of fat is present in the 
body. Part of the disintegration of proteids is due to the direct 
action of the circulating infective poisons on the tissues. 

3. In the febrile state the liver loses its glycogen and sugar. 

4. There is sometimes concentration of the blood, owing 
to sweating. The alkalinity of the blood is diminished owing 
to the presence of the organic acids already mentioned as ex- 
creted in the urine. 

5. The urine shows distinct changes. " Febrile " urine is 
diminished in quantity, datk in color, and deposits urates 011 
standing and cooling. The specific quantity is increased. 
These characters may, however, be absent if much water is 
drunk, or if pyrexia occurs in diseases associated with poly- 
uria, such as diabetes and granular contracted kidney. 

There is a diminished excretion of chlorids in the urine, 
except in rheumatic fever, typhoid fever, and malaria. This 
diminution does not as a rule last more than three days : only 
2.2 grams sodium chlorid may be found in the daily urine as 
compared with the normal 16.5 grams. There is an increased 
excretion of phosphates and potassium. The sulphates vary 
with the amount of nitrogen in the urine. The urine also con- 
tains pathological urobilin and reduced normal urobilin, which 
arise from the bile or blood-pigment. 

6. Albuminuria may be present : " febrile " or " toxic " al- 
buminuria (Giapter XVI.). Serum albumin and globulin 
are found, as well as casts, mainly hyaline. Albuminuria is 
most common in pneumonia, erysipelas, scarlet fever, diph- 
theria, smallpox, and typhoid fever; it also occurs in pus in- 
fection. Albumosuria may be found (Chapter XVI.). 

7. The urine sometimes gives the diazo-reaction, 
which is an orange-red to cherry-red color, developed 
on the addition to the urine of sulphanilic acid, sodium 
nitrite, and ammonia. The reaction is obtained most fre- 



46 CHANGES IN THE BODY TEMPERATURE IN DISEASE 

quently in typhoid fever, advanced pulmonary tuber- 
culosis, miliary tuberculosis, and measles. It is not 
common in pneumonia, scarlet fever, and diphtheria; and 
is very rare in rheumatic fever, meningitis, and ery- 
sipelas. The chemical substance which gives the reaction 
is unknown. 

The metabolic changes observed in different cases of pyrexia 
show, not adaptation to a new condition, but a disorganization. 
In fever the power of keeping the normal temperature is lost, 
owing to the action of the febrile agent. The disorganization 
which occurs is due to the action of the febrile agent on the 
heat nerve centers, which are closely associated with the vaso- 
motor center. In fever, therefore, thermotaxis, or the regula- 
tion of temperature, is disordered. That the vaso-motor center 
is affected in pyrexia is shown by many observations. When 
the temperature is rising and during the rigor, the skin is 
anemic and dry; in a falling temperature it becomes moist and 
hyperemic. During the early part of the pyrexia and the rigor 
the volume of a limb is diminished, as shown by actual measure- 
ment; during the fall of temperature the volume is increased. 
These changes in the volume of the limb are due to the quan- 
tity of blood present, and account for the fall of the surface 
temperature of the skin during the rigor, and its rise during 
the defervescence of the pyrexia. A fall of surface tempera- 
ture corresponds with an increase of internal temperature, and 
vice versa. Antipyrin and similar antipyretic drugs act by in- 
creasing the surface loss. Other evidence of the abnormal con- 
dition of the skin is shown in the production of laches cere- 
brates in pyrexia, as well as by the fact that reflex stimulation 
of the vaso-motor center does not cause dilatation of the cu- 
taneous vessels. 

Causes of Pyrexia. — Pyrexia is one of the conditions accom- 
panying inflammation. It may exist, however, in non-inflam- 
matory conditions. Acute inflammation is associated with 
fever. In chronic inflammation there may be no febrile rise, 
but there may be either an irregularity in the diurnal variation 
of the temperature, or slight pyrexia. 



CAUSES OF PYREXIA 47 

Though pyrexia is described as usually accompanying in- 
flammation, it is more correctly considered as the result of 
infection, of which, indeed, inflammation is a manifestation. 

Pyrexia may be considered as divisible into four classes : 

1. Pyrexia of nervous origin. 

2. Pyrexia of unexplained origin ; traumatic fever ; ure- 
thral, etc. 

3. Pyrexia due to autointoxication, or to degenerative pro- 
cesses. 

4. Infective, bacterial, or inflammatory pyrexia. By far the 
largest number of cases belong to this group. 

This classification, which is not completely satisfactory, 
attempts to divide pyrexia as to its cause. 

1. Pyrexia due to Injury or Disease of the Central Nervous 
System {Non-inflammatory) . — Brain. — In cerebral hemor- 
rhage a rise of body temperature occurs. There is an initial 
fall of the internal temperature, which, in some fatal cases, is 
not followed by a subsequent rise. In non-fatal cases, the initial 
fall of a few degrees is succeeded by a moderate rise, ioi° to 
1 03° F. In other cases, the rise goes on to hyperpyrexia, and 
is continuous till death. Hemorrhage into the pons is the 
commonest cause of this variation of temperature, but it is 
also observed when the basal ganglia are affected. Febrile 
rise of temperature is also observed in tumors of the pons. 
It is doubtful whether the rises of temperature in disseminated 
sclerosis are due to the injury to the nervous system, or to 
autointoxication. 

Tumors in the region of the cervical cord, or injuries to this 
part, lead to a rise of body temperature and sometimes to hy- 
perpyrexia. In these conditions, where there is direct injury 
to the central nervous system, the rise of temperature 
must be ascribed to the direct damage to the centers or to the 
nerve fibers. 

2. Pyrexia of Unexplained Origin. — Traumatic Fever is 
used in two senses, according as there is, or is not, obvious 
infection and septic absorption. In cases where there is no 
obvious septic absorption from the injury, it must be remem- 
bered that a severe injury mav lead to intoxication from the 



48 CHANGES IN THE BODY TEMPERATURE IN DISEASE 

intestines, so that cases of traumatic fever may really come 
under the heading of infective fever. 

The causation of urethral fever, where not obviously septic, 
is also unexplained, as well as the rise of temperature that 
occurs in certain functional nervous conditions. It must be 
remembered that the disintegration of proteids in the body 
may give rise to substances which are poisonous, and some of 
these may be fever-producing. Fever is produced by the injec- 
tion of lamb's blood into man. Some such explanation may 
be hazarded as the cause of the fever in pernicious anemia, 
leukemia, and lymphadenoma, where there is no obvious infec- 
tion. Not sufficient, however, is known of these conditions to 
enable any discussion to be made of the cause of the pyrexia, 
nor of that which occurs in cirrhosis of the liver, and some 
cases of jaundice and sarcoma. 

3 and 4. Infective Fever, Zymotic Fever, Toxic Fever. — The 
chief agents producing fever are the products of infective 
agents. In 1865 Otto Weber and Billroth showed that the 
injection of septic material into animals caused a febrile rise 
of temperature. In 1857 Bur don Sanderson separated from 
putrefying material a substance he called pyrogen, the in- 
jection of which into animals caused fever. Later, it was 
found that Schmidt's febrin ferment caused fever; and the 
idea arose that the febrile agent was of the nature of a 
ferment. 

The products of bacteria and their action are discussed 
elsewhere (Chapter IV.). It may be repeated here that the 
excretory products of bacteria are, in many instances, fever- 
producing. Attention may be drawn to the fact that some 
of these will, in one case, quickly reduce the temperature, and 
in another case cause a febrile rise. Thus, in rabbits, the 
typhoid toxin causes a great fall of temperature whilst in 
man it produces a febrile rise. 

The products of the digestive action of bacteria do not act 
alike. The albumoses are fever-producing, whether given 
in single or multiple doses. In multiple doses, they tend to 
produce a continued rise of temperature. The albumoses of 
ordinary peptic digestion are also fever-producing agents. 



CAUSES OF PYREXIA 



49 



When the proteids are split up beyond the stage of 
albumoses, in only rare instances are the products fever- 
producing. The anthrax base does not produce fever. 

Of alkaloids that produce a slight rise of temperature, 
strychnin, atropin. and cocain may be mentioned, as well as 
mydalein. which is one of the products of putrefaction. 

The fever-producing products of bacterial action have a 
special action on the central nervous system, and, no doubt, 
it is partly to this action that they owe their property of dis- 
organizing the heat centers. 



CHAPTER III 

INFECTION 

I. The Infective Agent 



Infection may be defined as the invasion of the body by living 
agents, which multiply in various parts of the body and produce 
symptoms by forming toxic substances. Infection may be con- 
sidered as a part of the subject of parasitism, which includes 
both animal and vegetable agents which develop in the body. 
Animal parasites produce their effects either by causing 
hemorrhage from a mucous membrane, by blocking vessels, 
or, when growing in the tissues, by destroying the proper ele- 
ments of the organ. Their effects are mainly local. The 
disease caused by the echinococcus is not an infection, but a 
purely local growth, and no poisons are produced which cause 
symptoms. The presence of a tapeworm in the intestinal tract 
produces no symptoms by poisoning, and the same may 
be said of all the larger animal parasites. On the other hand, 
some forms of animal parasitism approach the conditions of 
infection. Excluding the consideration of the parasite of 
malaria, trichiniasis may be considered as partly an infection, 
inasmuch as the symptoms produced are those usually associ- 
ated with the infective process, such as fever and wasting, and 
edematous swelling of the muscles ; and a form of trypanosoma 
has been described as causing disease with symptoms of infec- 
tion. The filarial parasites are not known to produce symptoms 
when found in the blood, but are sometimes associated with 
definite symptoms, as in the sleeping sickness of the West Coast 
of Africa. The tsetse-fly disease is also associated with definite 
symptoms. These, however, may be mainly due, as in filaria, 

50 






CLASSIFICATION OF PARASITES 



5i 



to the mechanical action of the parasite in the blood, and they 
have as yet not been shown to produce chemical poisons. 
Parasites may be divided into infective and non-infective.* 

1. Infective Parasites. — Micro-organisms, ameba, some 
protozoa, some animal parasites ( ?). 

2. Non-infective Parasites. — Animal parasites generally, 
some micro-organisms (molds). 

The present article will deal solely with infective parasites, 
of which the micro-organisms form by far the largest number. 

Micro-organisms may be divided into three classes: (1) 
Hyphomycetes, or molds; (2) Blastomycetes, or sprouting 
fungi; (3) Schizomycetes, or cleft fungi. 

1. Hyphomycetes. — These fungi consist of long filaments, 

* Parasites are distinguished from saprophytes., the point of distinction 
being that parasites exist in. and live on, only living tissues, while sapro- 
phytes live on dead animal or vegetable tissue. Examples occur of para- 
sites which are obligatory, that is, can only exist in all their stages as 
parasites, whether these stages occur only in one animal, or in more than 
one animal. 

On the other hand, parasites may be facultative saprophytes; that is, 
usually existing as parasites, they are yet capable of living on dead animal 
or vegetable tissue. 

Saprophytes may be obligatory, examples of which do not usually occur 
in disease. 

They may also be facultative parasites, that is, although usually sapro- 
phytes, they may become parasites. 

The following examples may be given as illustrations : 

1. Obligatory Parasites. — Infective agents of erysipelas, gonorrhea, 
rabies, variola, scarlet fever, measles, glanders. 

2. Facultative Parasites. — Infective agents of tuberculosis, actinomycosis, 
pus infection, diphtheria. 

3. Facultative Saprophytes. — Infective agents of anthrax, tetanus, typhoid 
fever, cholera. 

These terms, which include both animal and vegetable parasites, are 
only used in the relation of the parasite to the diseased condition it pro- 
duces in the living body. They do not refer to any possible cultivation 
of the infective agent, which must necessarily be on artificial media, but 
it may be said generally that the more obligatory a parasite is, the less 
likely is it to be capable of cultivation in an artificial medium. Many of 
the micro-organisms which might be considered obligatory parasites can be 
artificially cultivated, although they may not pass any vegetative existence 
outside the living body. 



52 INFECTION 

which are interlaced into a mycelium. They are reproduced 
by means of spores attached to specially developed hyphse. 
Some of these fungi produce a purely local effect, on the skin, 
the hair, and the mucous membrane of the mouth. These are 
trichophyton megalosporon ectothrix, T. megalosporon endo- 
thrix, and microsporon Audouini which are the cause of ring- 
worm; achorion Schonleinii, the cause of favus; monilia 
Candida, which produces thrush; microsporon furfur, which 
causes pityriasis versicolor, and some species of mucor, which 
are found in the auditory meatus in association with ear disease. 
The disease which these fungi produce is purely local, and does 
not become generalized in the internal organs of the body. 

Some of the hyphous fungi ferment carbohydrates, chang- 
ing starch into sugar. These are penicillium glaucum, which 
is non-pathogenic, monilia Candida, mucor, aspergillus niger, 
and aspergillus fumigatus. Another genus, oidium lactis, is 
non-pathogenic, and is the cause of the souring of milk. 

Some hyphous fungi are capable of existing in living tis- 
sues and of producing disease which may cause death. These 
are aspergillus, actinomyces, and streptothrix. 

Aspergillus has been found in the lung, being the cause 
of pneumonomycosis, but it has also been found in pus from 
the middle ear and antrum, and in tuberculous cavities in the 
lung. One of the two species of aspergillus (A. niger) has 
also been found in skin lesions, in the cornea, in the intestine, 
and in the spine, causing Pott's disease. A. niger has been 
found by most observers as possessing very slight pathogenic 
properties. A. fumigatus will grow well in the living body, 
and will produce death when injected into animals. 

Actinomyces is the cause of the disease actinomycosis, 
which occurs in man, horses, cattle, and pigs. It is a hyphous 
or rayed fungus, and in some forms resembles a coccus. It 
was first discovered in 1876 in cattle, by Bollinger, and in 
1877 by Israel. In 1879 Pontick found the fungus in lesions 
in both cattle and man. It is a disease of temperate climates, 
and the fungus produces granulation tissue containing giant 
cells and epitheloid cells, with formation of pus. Thick con- 
nective tissue surrounds the lesions, which are slow in forma- 






ACTINOMYCOSIS 53 

tion. The infection is carried from the awn of barley and 
other cereals to both cattle and man, but there is also direct 
infection from cattle to man. The infection takes place 
through wounds or excoriations of the mucous membrane 
and skin, through carious teeth, by inhalation, or by means 
of the alimentary tract. The parts affected in man are: face 
and neck and lower jaw in about 52 per cent, of the cases; 
the alimentary tract in about 23 per cent, (cecum and appen- 
dix) ; respiratory organs in about 13 per cent., producing 
purulent bronchitis, and in other cases masses in the lung 
spreading to the pleura and pericardium. The tongue is 
affected in rather more than 3 per cent, of cases; the skin in 
about 3 per cent, and other parts, such as the spine, in a much 
smaller proportion. 

Granules which consist of the fungus occur in the pus from 
the lesions of actinomycosis. These granules are from 2 to 
6 millimeters in diameter, or from -5V to 4V of an inch, by zli> 
to rh of an inch. The fungus may be cultivated from the 
pus on artificial media, and either from this cultivation or 
directly from the lesion the disease may be conveyed to ani- 
mals, or it may be inoculated from man to the rabbit, or from 
cattle to cattle. The disease spreads by gradual invasion and 
destruction of an important part of the tissues, and causes 
death, partly in this manner, but also in part by a chronic in- 
toxication, as shown by irregular pyrexia and wasting. Metas- 
tasis of the lesion is not common. 

Mycetoma, or Madura-foot, is a disease pathologically re- 
sembling actinomycosis. It is due to the growth of a fungus 
called streptothrix madurae, resulting in the formation of 
nodules and a thin pus. 

Other forms of streptothrix have been found in lesions both 
in man and animals. All these conditions have the charac- 
teristic of being local formations. 

2. Blastomycetes. — These are ovoid cells, which multiply by 
budding, or by the formation of endogenous spores. Saccharo- 
myces induce alcoholic fermentation. The torulse do not 
form spores : they act as ferments. Mycodermata have but 
little action. Yeasts are found in the human bodv; in some 



54 INFECTION 

cases in the urine and feces, and in the dilated stomach. The 
variety which is found in these cases is the one common in the 
air (saccharomyces ellipsoideus). 

A form of blastomyces has been described in carcinoma, 
existing within the cells, and capable of being cultivated in 
some instances and of producing lesions when inoculated into 
animals. They also appear to produce some forms of local 
dermatitis (blastomycosis), but, according to our present 
knowledge, blastomycetes play but an insignificant role in the 
production of disease. 

3. Schisomycetes, or Bacteria. — Most of the infective agents 
which produce disease belong to this class, and are composed 
of small cells, with no chlorophyll and no visible nucleus. The 
protoplasm in some forms is not uniformly distributed within 
the cell wall, and shows breaks; a condition referred to as 
plasmolysis. The varieties of bacteria are coccus, bacillus, and 
spirillum. 

Coccus. — Cocci receive different names, according to the 
grouping of the individual elements, which are usually spherical 
in shape, and vary in size considerably in different forms. The 
diplococcus is arranged in pairs, the streptococcus in chains, the 
tetracoccus in fours, the sarcina in masses of eight or more, 
and the staphylococcus either singly, or in groups of numerous 
elements. Some of the group forms are encapsuled. Though 
it is convenient to divide the cocci into these different groups, 
the division is not of as much importance as the action of the 
individual micro-organism. Whereas sarcina may be inert 
streptococcus and diplococcus may induce infection in a vary 
ing, but virulent degree. The individual grouping of the coc 
cus is also not constant, and the grouping of one particular 
form may pass into another form, under cultivation. This vari- 
ation of form, however, does not mean identity of all the forms 

Bacillus. — Bacilli are rods varying in shape and size, and 
may, in some instances, form threads almost like a mycelium. 
Some are immobile; others are mobile, owing to the presence 
of cilia or flagella. 

Spirillum. — Spirilla are curved forms, the best pathogenic 
example of which is the cholera vibrio. 



PATHOGENIC BACTERIA 



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60 INFECTION 

Mode of Growth of Bacteria. — The mode of growth of 
bacteria must be considered from the point of view of growth 
in artificial media, and of that of growth in the body. 

In artificial media the growth and vitality depend on 
the temperature, the presence or absence of oxygen, on 
exposure to sunlight and on the chemical composition of 
the nutrient medium. Most pathogenic bacteria grow best 
at a temperature of from 37° to 38° C. A higher tempera- 
ture is not beneficial to them, and many will not grow below 
a temperature of from 20 to 22 C. Some, for example 
the glanders bacillus, lose their virulence when exposed to a 
temperature below 37° C. This relation to temperature is 
intensified in the so-called thermophilic bacteria, which are 
usually non-pathogenic, and which do not grow except at a 
temperature of 50° C. 

The necessity for a certain degree of temperature (37° C.) 
for the active development of pathogenic bacteria is of great 
importance, inasmuch as it is at this temperature that they 
develop in the body. Some of the less specialized forms of 
bacteria, for example the typhoid bacillus and the colon bacil- 
lus, "will withstand exposure to very low temperatures, but no 
living bacillus will withstand a temperature of 6o° C, if 
applied in a liquid medium for some minutes. Spores, how- 
ever, are not killed at this temperature, and require a higher 
temperature (ioo° C.) and a longer exposure. 

Relation to Oxygen. — The relation of the growth of bacteria 
to the amount of oxygen present in the medium in which 
they grow, is of great importance. Most pathogenic bacteria 
grow in the presence of oxygen, and so are called aerobic. 
Others grow in the absence of oxygen (anaerobic), this being 
excluded by substituting an atmosphere of hydrogen, carbon 
dioxid. or nitrogen. 

For the active growth of some micro-organisms oxygen is 
essential, and so they are called obligatory aerobes. The best 
example of this is the bacillus subtilis, which is non-patho- 
genic; many other examples occur among non-pathogenic 
bacteria. Most pathogenic bacteria, although aerobic, are 



CONDITIONS OF GROWTH OF BACTERIA 61 

capable of growing in the absence of oxygen, and so are called 
facultative anaerobes. Examples of these are pus cocci, pneu- 
mococcus, bacillus anthracis, the typhoid bacillus, the colon 
bacillus, and the vibrio of Asiatic cholera. A few pathogenic 
bacteria grow only when oxygen is excluded, and so are called 
obligatory anaerobes. Examples of these are the tetanus 
bacillus, the bacillus of malignant edema, the bacillus of 
quarter-evil and the bacillus enteritidis sporogenes (Klein). 

The condition of growth in the body for pathogenic 
bacteria is, of course, dependent to some extent on the 
amount of oxygen present. The tissues of the body contain 
oxygen in more or less firm combination, the red blood 
corpuscles containing it in the largest proportion. The 
amount of oxygen which is present in the tissues is rela- 
tively small, so that the bacteria of the body are not ex- 
posed to the same amount of oxygen as they are in a culture 
medium, which itself contains free oxygen and is. moreover, 
exposed to the air. 

In this connection it is interesting to note that, although 
most pathogenic bacteria are aerobes, they are also facultative 
anaerobes. The amount of oxygen in the tissues does not 
necessarily prevent the spread in the body of obligatory 
anaerobes. Thus, although the tetanus bacillus grows onlv 
in the region in which it is inoculated, and this want of further 
spread may be partly due to the small amount of oxygen pres- 
ent in the tissues, yet the bacillus of malignant edema, which 
is a similar organism in its relation to oxygen, spreads to the 
subcutaneous and neighboring tissues. The main factor in 
limiting the growth of bacteria in the body is not the presence 
or absence of oxygen. 

The Effect of Sunlight. — Direct or diffused sunlight 
destroys bacteria, especially the blue and violet rays. Even 
spores may be destroyed. The tubercle bacillus is destroyed 
in a few minutes to one hour by exposure to direct sunlight. 
and in five to seven days by exposure to diffused sunlight 
(Koch'). The typhoid bacillus, the colon bacillus, the bacillus 
pyocyaneus. the vibrio of Asiatic cholera are destroyed by 



62 INFECTION 

four to seven hours' exposure to direct sunlight. If the spores 
of anthrax be inoculated into a gelatin plate, and part of 
the surface exposed to direct sunlight or to an electric arc 
light for two to six hours, they are killed, inasmuch as when 
cultivated the plate remains sterile over the exposed area 
(Marshall Ward). 

The times which have been given for the killing of the 
bacteria by exposure to sunlight are not correct when the 
bacilli are mixed with organic matter, as, for example, when 
the tubercle bacillus is in the sputum, or the typhoid bacillus 
and cholera vibrio are in the motions or urine. The time 
required for the killing of the bacteria under these conditions 
is much prolonged, and death of the bacteria may not occur 
before the organic matter is nearly dry. 

Effect of Nutrient Medium. — With those pathogenic micro- 
organisms which are capable of being cultivated, besides the 
question of oxygen, which has already been considered, the 
culture medium must be of a certain composition to insure 
good growth. It must contain proteid substances, such as 
peptone, albumoses, albumin, or fibrin; it must be slightly 
alkaline or neutral (although some bacteria can grow in a 
slightly acid medium), and must contain a certain proportion 
of mineral salts, chlorids of sodium and potassium, calcium 
and magnesium phosphates. As regards the salts requisite, 
sodium chlorid and calcium phosphate are a necessity for the 
vitality of protoplasm. Without sodium chlorid a living cell 
cannot exist, and calcium phosphate bears a peculiar and essen- 
tial relation to certain transformations of proteids such as the 
clotting of milk and blood, as well as to the growth of tissues. 
The proportion in which the salts must be present is practically 
that in which they exist in the blood, namely, about 0.8 gram 
per cent., but an excess of phosphates does not, as a rule, inter- 
fere with the growth of bacteria. 

The reaction of the medium is of great importance. It 
is usually made slightly alkaline or neutral to litmus. Some' 
pathogenic bacteria are very sensitive to the reaction of the 
medium. The anthrax bacillus will grow in neutral solution, 



CONDITIONS OF GROWTH OF BACTERIA 63 

or even one moderately alkaline; the diphtheria bacillus will 
grow in a slightly acid, neutral, or moderately alkaline solu- 
tion; whereas, for the tetanus bacillus, the medium must be 
made as nearly neutral as possible. On the other hand, the 
typhoid bacillus and the colon bacillus, although growing best 
in a slightly alkaline medium, will develop in a medium of 
which the acidity is due to hydrochloric acid, the colon bacillus 
being more resistant than the typhoid. 

The presence of nitrogenous substances, usually in the 
form of proteids, is necessary for the development of patho- 
genic bacteria. The substances usually used are commercial 
peptone (which consists chiefly of albumoses), the serum pro- 
teids, and gelatin. In some cases the addition of glycerin 
to the medium stimulates the growth of bacteria; in other 
cases sugar acts as a stimulant. A small proportion of fat 
is also present, so that, in some instances, the bacteria appear 
to require for their proper growth the same three food stuffs, 
proteids, fats, and carbohydrates, which are necessary for the 
vitality of the animal cell. This is in contrast to the con- 
ditions of existence of most non-pathogenic bacteria. Many 
of these, especially those present in the air, will flourish in 
liquids containing only mineral salts, with some tartrate, as 
in Pasteur's fluid. Others, again, such as the putrefactive 
bacteria, require proteid substances for their proper growth, 
and with certain specialized bacteria, such as the nitrifying 
organisms, a culture fluid of sulphate of ammonium, phosphate 
of potassium, and magnesium sulphate, is necessary, with or 
without silicic acid. 

What effect a pathogenic bacterium has on the medium in 
which it grows is more properly discussed under the heading 
of Bacterial Products (Chapter IV.). It may here be said 
that they do not have any appreciable effect on the peptone. 
Many, however, digest albumin and gelatin. 

Bacteria Outside the Body. — Pathogenic bacteria may, as a 
rule, be considered highly specialized forms, the life of which 
has been altered by the conditions in which they exist in 
disease. Originally they must have arisen from forms similar 
to the non-pathogenic bacteria now known. Most pathogenic 



64 INFECTION 

bacteria which produce a definite disease may be said to 
pass all their active existence in the animal body, and in the 
course of the disease itself. Most do not live for any length 
of time in the dead body, although in this respect some are 
more sensitive than others. Some even may disappear from 
the living body before death occurs, as in some cases of 
diphtheria and tetanus. Others, again, such as the pus cocci, 
have a great vitality. The same may be said of the anthrax 
and tetanus bacilli, owing to the spores they produce out- 
side the body, of the typhoid bacillus and of the colon 
bacillus. 

Very few of the pathogenic bacteria have a prolonged 
existence outside the body, that is, they do not have a 
saprophytic existence under natural conditions. This is 
probably because the conditions of food and light are un- 
favorable. The best example to the contrary is the tetanus 
bacillus, which is found in some kinds of soil. The pus 
cocci (staphylococcus) also exist in the air, chiefly in towns 
and buildings, and, as sources of infection, come from dust 
and previously existing abscesses. The tuberculosis bacillus 
has, as far as is known, a very short existence outside the 
body. The same is true of the glanders bacillus and the 
diphtheria bacillus, but in none of these cases is there any 
evidence that the bacillus can grow outside the body, except 
in specially prepared culture media. This is not to be won- 
dered at in the case of the tuberculosis bacillus, which requires 
specially prepared culture media (serum or glycerin agar), 
nor of the glanders bacillus, which soon becomes non-virulent 
when removed from a temperature of 37° C. 

The colon bacillus and allied forms appear to have a separate 
existence in nature, as they are found in contaminated water 
and in sewage; but many of the forms which have been 
described are not the same as the one found in the intestinal 
tract; and the true pathogenic colon bacillus lives only a short 
time in sewage and soil. The typhoid bacillus is also resistant 
to external conditions. It will not live for any length of 
time in water nor in soil, in the latter case being beaten 
out by the other bacteria present; but if the bacteria are few, 



VARIABILITY IN VIRULENCE OF BACTERIA 65 

the bacillus may retain its vitality for a considerable time, as 
in damp rags and linen, and in an ordinary broth culture it 
will live for many months exposed to daylight and at the tem- 
perature of the laboratory. 

Variability in Virulence of Bacteria. — Cultures of bacteria 
obtained from disease exhibit very varying degrees of virulence 
when injected into animals, and this variability is shown in 
different ' ways. A pathogenic bacterium, even if it forms 
spores, may, by being kept in culture, soon lose its virulence, 
so that it will not be fatal when injected into animals. This 
degeneration of the culture may be ascribed partly to the 
medium in which it is grown, and partly to exposure to air 
and light, inasmuch as if the bacteria are given their natural 
culture medium, that is, the animal body, their virulence may 
be recovered. All the forms of bacteria show this degenera- 
tion in artificial culture, and the decrease of virulence is 
sometimes accompanied by a change of form, the so-called 
involution forms being observed. This is noticeable in the 
diphtheria bacillus, in which the clavate forms become en- 
larged and attenuated in parts; with the tetanus bacillus, in 
which a similar change occurs; with the tuberculosis bacillus, 
in which the bacilli may grow into long threads of but little 
virulence; and with the plague bacillus. 

The virulence of bacteria depends on their power of 
producing their characteristic poisons, and they do this much 
more efficiently in the animal body than in artificial culture 
media, however suitable these may be for their vegetative 
growth. The pneumococcus and streptococcus are examples 
of micro-organisms which rapidly lose their virulence when 
grown in artificial culture media. This they do in one or two 
day?. 

Artificially, the virulence of a bacterium may be attenuated 
or increased. The methods of attenuation used are heat or 
certain antiseptic substances, which partially inhibit the 
growth. Pasteur, for example, attenuated the anthrax bacillus 
by growing it at a temperature of 42° C. for over three weeks, 
and so produced his premier vaccin, in which no spores were 
5 



66 INFECTION 

formed. The diphtheria bacillus and the tetanus bacillus have 
been attenuated by exposing the culture to the action of 
tri-chlorid of iodin or of phenol. Methods of attenuation are 
now mainly of historical interest, but were adopted as a means 
of producing immunity in animals, the injection of the atten- 
uated virus producing a slight disease which protected the 
animal against the severe disease (Chapter VI.). The prod- 
ucts of the attenuated micro-organism and of the virulent 
are practically the same. What the method of attenuation 
apparently does is to lessen the vitality of the bacterium, so 
that it produces a smaller amount of poison. 

Methods of increasing the virulence of bacteria are of 
more importance. The chief method is one of passage 
through a series of animals. This may be done either by 
using the culture of the bacterium, injecting a large dose 
into one animal, and, on the death of the animal, injecting 
the exudation produced by the bacterium into a second 
animal, and so on. Thus the cholera vibrio may be intensi- 
fied in virulence by injecting a fresh broth culture into the 
peritoneal cavity of a guinea pig. On the death of the 
animal, the peritoneal exudation produced is injected into a 
second animal, or, if sufficient exudation is not present, it 
may be inoculated into broth, allowed to grow for a few hours, 
and then injected into a second animal, and so on. In this 
way, after a series of animals, perhaps twenty or thirty, have 
been done, it is found that an infinitesimal dose of the culture 
or exudation will cause death, usually in from sixteen to eigh- 
teen hours; the virulence being increased twenty or thirty 
times. This death is more rapid than that usually produced 
by an infective agent, and the explanation seems to be that, 
with the living bacteria is injected a fatal dose of the chemical 
poison. The virulence of the pneumococcus and streptococcus 
have also been increased in this manner by subcutaneous injec- 
tion, and most of the other bacteria may be intensified in viru- 
lence by this method. 

Another method is to aid the action of the bacterium by 
injecting at the same time the chemical products of another 
bacterium. Thus, in the case of the typhoid bacillus, its 



VARIABILITY IN VIRULENCE OF BACTERIA 67 

virulence may be intensified by injecting intraperitoneally 
a small quantity of the broth culture of the bacillus, and 
subcutaneously a sterilized broth culture of the streptococcus 
pyogenes or the bacillus prodigiosus. The subsequent pro- 
cedure is the same as in the other passage experiment. The 
animal dies, the typhoid bacillus is recovered from the peri- 
toneal exudation, and is injected into a second animal, a 
subcutaneous injection of the products of the streptococcus 
being also made. After a certain number of animals have 
been used, it is found that a smaller and smaller quantity of 
the products of the streptococcus and of the culture of the 
typhoid bacillus have to be used, and eventually the typhoid 
bacillus may be injected by itself, and will produce death. A 
further increase of virulence may be obtained by continuing 
the series of animals with the bacillus alone. The degree of 
virulence to which the bacteria can be raised is astonishing. 
A fraction of a cubic centimeter of a broth culture, or a single 
platinum loopful of a solid culture, will be found to cause death 
in from sixteen to eighteen hours. It may again be said that 
the rapid death in these cases is due, in part, to the chemical 
poison which is injected in addition to the living bacillus. 

From the lesions produced by bacteria in the animal body 
cultures are obtained which vary considerably in virulence. 
Thus, from an abscess, a streptococcus may in one case be 
obtained which is very virulent, being rapidly fatal to animals 
when injected; in another case, a culture ma}^ be obtained 
which is only fatal to animals after the virulence has been 
intensified. The same may be said of the diphtheria bacillus, 
but the variations in virulence are not so marked as in the 
case of the streptococcus. In typhoid fever cultures of the 
bacillus obtained from the spleen immediately after death, and 
injected into animals, show great variations in virulence. 
In some cases the micro-organism produces rapid death; in 
others it will only do this after intensification. This varia- 
tion in virulence is not due to any manipulation outside the 
body, inasmuch as it is only a question of a few hours after 
removal from the body before the material is used for experi- 
ment. 



68 INFECTION 

The variability in virulence which is found in actual 
disease may be dependent on different conditions, either on 
the fact that the virus which produced the disease was not 
virulent, or that the virus had become attenuated in the body 
by the resistance to its growth, or by the degeneration of 
bacteria which occurs in long-standing lesions, such, for ex- 
ample, as abscesses and some tuberculous lesions. 



CHAPTER IV 

infection — continued 

II. The Chemical Products of Bacteria and their Action 

Bacteria produce their effect in disease by means of the 
chemical poisons which they form. Some of the poisons pro- 
duced are of a highly complex nature, and are closely related 
to certain poisons produced by animal cells and by plants, such 
as snake venom, abrin, ricin, and robin. 

In addition to the formation of these highly complex 
poisons, the process of putrefaction must be considered, and 
some simpler transformations, both of carbohydrates and of 
certain nitrogenous substances, such as urea and ammonia. 
Many of the processes may be accurately described as fer- 
mentation, the process by which the secretion of a cell pro- 
duces a rapid chemical change in the substances on which it 
acts. In fermentation it may be considered that the process 
is one in which a complex body is broken up into simpler 
chemical forms, but in some cases in which bacteria form very 
active poisons, the evidence of fermentation is not at present 
forthcoming. 

Simple Bacterial Fermentation. — The simpler forms of 
bacterial fermentation are instanced by the alcoholic, lactic 
acid, butyric acid, and acetic acid fermentations, as well as 
the fermentation of urea. In the alcoholic fermentation, yeast 
transforn^s cane sugar into dextrose and levulose, and breaks 
up dextrose into alcohol and various bv-products, which are 
chieflv organic acids. From yeast can be separated the active 
agent which transforms cane sugar into dextrose and levulose. 
The breaking up of the dextrose into alcohol and other prod- 

6 9 



70 INFECTION 

ucts is a property of the yeast cell itself : but by expression, 
a ferment (zymase) has been obtained from the yeast-cell, 
which has this property (Buchner), The transformation takes 
place according to the following formula : 

C H 12 O 6 = 2 c 2 A 6 o + 2 co 2 

Glucose Alcohol + Carbon dioxid. 

Glycerin, succinic acid, and fusel oils are formed at the same 
time. 

The lactic acid fermentation, which occurs in the produc- 
tion of sour milk, is caused by the bacillus acidi lactici. Lac- 
tose is transformed into lactic acid and by-products. Glucose 
is also transformed into lactic acid. The formulae usually 
given for this transformation are as follows : 

C ia H a3 0„ + H 2 = 4 C s H 6 O s . 
Lactose -f~ Water = Lactic acid. 

CeHisOe = 2 C3H6O3. 

Glucose = Lactic acid. 

These formulae, however, do not represent the complete 
transformation, inasmuch as some of the by-products, such 
as CO, and H 9 , are not allowed for. 

The butyric acid fermentation is- produced by the bacillus 
butyricus. In the ordinary course of events in milk it follows 
the lactic acid fermentation, and lactic acid is transformed into 
butyric acid, with the production of carbonic acid and hydro- 
gen as by-products. 

The formula for the transformation is as follows : 

2 C 3 H 6 3 = C 4 H 8 9 + 2 C0 2 + 2 H 2 

Lactic acid = Butyric acid -\- Carbon dioxid 4- Hydrogen. 

The acetic acid fermentation is produced by the mycoderma 
aceti, which breaks up alcohol into acetic acid and other 
products. 

The lactic and butyric acid fermentations play some part 
in disease, inasmuch as they occur in the stomach contents in 
cases of obstruction of the pvlorus, and also in the small in- 
testine in some cases of indigestion of food. 

Another simple fermentation which is produced by a bac- 






NITRIFICATION 71 

terium (micrococcus urese) is the transformation of urea into 
ammonium carbonate, according to the following formula : 

CO(NH 9 ) a -f 2 H a O = (NH 4 ) a C0 9 

Urea + Water = Ammonium carbonate. 

The ammonium carbonate is further split up into ammonia 
and carbonic acid, probably, however, not by the micrococcus. 
This change occurs in the ammoniacal decomposition of urine, 
and is really due to a ferment which is excreted by the micro- 
coccus. This ferment may be precipitated by alcohol, and is 
thus separated from the bacterium. It has been found to 
produce the same effect as the bacterium itself. 

There are several examples in the vegetable kingdom of non- 
living ferments producing a chemical change in substances. 
Thus, the ferment known as emulsin splits up amygdalin in the 
presence of water into oil of bitter almonds and prussic acid. 

Nitrification. — Some bacteria have a special action on am- 
monia and nitrates. The most common action is the oxi- 
dation of ammonia, with the production of nitrites and nitrates. 
The following bacteria produce nitrites : 

B. prodigiosus, Deneke's spirillum, Finkler Prior's spirillum, 
the B. anthracis and staphylococcus pyogenes. 

Some bacteria, c. g. vibrio cholerae asiaticae and vibrio 
metchnikovi reduce nitrates to nitrites. 

Nitrification, however, is a special property of certain 
bacteria in the soil, and when grown in special media (p. 63). 
These have been called nitrosomonas (producing nitrites) and 
nitrobacter (producing nitrates). An important effect is ob- 
served in the production of the nitrates of the soil from the 
ammonia of decaying animal matter. 

Putrefaction. — There are a large number of bacteria which 
cause putrefaction with the formation of a foul, decomposing 
mass. Putrefaction affects proteid substances, but not carbo- 
hydrates or fats. It cannot take place without the action of 
bacteria, for although there are some slight changes in chemi- 
cal properties observed in solutions of proteids kept for a long 
time, these are but slight in comparison with the great 



72 INFECTION 

changes which occur rapidly in putrefaction and result in the 
formation of numerous bodies from the proteid molecule. 

Putrefactive bacteria are both aerobic and anaerobic, and 
in a particular putrefying mixture it is not infrequently 
observed that the aerobic bacteria develop first, and, having 
exhausted the oxygen in the liquid and formed a scum on 
the surface, they lead to the development of the anaerobic 
forms. As the proteid matter becomes exhausted, the bacteria 
diminish, and when all the food is finished, bacterial develop- 
ment ceases to a great extent, sometimes completely. The 
main putrefying micro-organisms are : 

The various forms of proteus : P. vulgaris, P. Zenkeri, and 
P. mirabilis; as well as B. pyogenes fetidus, B. saprogenes, mi- 
crococcus fetidus. These are only a few of the putrefactive bac- 
teria, and a large number have not yet been exhaustively studied. 

Putrefaction is a rapid process, and, inasmuch as it affects 
the complex molecule of proteids, it is to be expected that a 
great variety of chemical products would be formed. 

Proteids consist of C. H. N. O. S. and sometimes P., and 
the products of putrefaction may be divided into two classes — 
the nitrogenous and non-nitrogenous. The non-nitrogenous 
consist of gases, such as carbonic acid, hydrogen, sulphureted 
hydrogen (H 9 S) and marsh gas (CH 4 ); and of organic acids, 
such as formic acid (CH 2 2 ), butyric (C,H 8 CO and valerianic 
acids (C B H, O,), of the fatty series; as well as lactic (C s H fl O a ), 
succinic (C 4 H 6 4 ), glutaminic (C B H,(NH 2 )0 4 ) and aspartic 
(C 4 H 7 N0 4 , amido-succinic) acids. Glutaminic and aspartic 
acids, it will be noted, are nitrogenous (amido) compounds, 
and may be produced artificially by boiling proteids with sul- 
phuric acid. 

The other nitrogenous products fall into different groups. 
Free nitrogen is produced, as well as free ammonia. Bodies 
of the aromatic series, some of which are foul-smelling (such 
as indol and skatol) and tyrosin, form another group. The 
third group would include bodies which have been called 
ptomains or cadaveric alkaloids, many of which are com- 
pound ammonias. The fourth group contains the early prod- 
ucts of the digestion of proteids, namely, albumoses. 



PRODUCTS OF PUTREFACTION 73 

Ptomains. — A large number of these bodies have been de- 
scribed, and at one time they were supposed to play a great 
part in the production of the symptoms in infective disease 
due to bacteria. Although this has been proved not to be the 
case, the ptomains are of some importance in disease, although 
many of them possess no poisonous action. 

Neuridin is very commonly found in putrefying mixtures, 
but is not poisonous. It is isomeric with cadaverin, which has 
been found in cholera cultures and in the urine in cases of 
pernicious anemia. 

Cholin (C 5 H 1B NO a ) is also frequently found, and is one of 
the most important of these bodies. It has been found in 
cholera cultures, and there is evidence that it is present in the 
cerebrospinal fluid in cases of general paralysis of the insane 
(Chapter XIX.). It is obtained from the bile, and is widely 
distributed in the animal body in lecithin, a compound of cholin 
with glycero-phosphoric and other acids. 

Another substance, neurin (C 5 H, 3 NO) has a similar action 
to cholin, although not so powerful. It is formed by the de- 
composition of cholin, and cholin is related to muscarin, which 
may be considered as oxycholin (C 2 H 3 (OH) 2 , N(CH 3 ) 3 , OH), 
and is formed by oxidizing cholin with nitric acid. In frogs 
cholin causes paralysis, and atropin antagonizes its action. 
Its general action in higher animals is that of producing 
diarrhea, and of affecting the secretions, causing salivation, 
lacrimation, and sweating. The respiration is affected; there 
is a fall in blood pressure with cardiac failure, while an 
effect on the nervous system is shown in the production of 
clonic spasms. 

Methylamin, dimethylamin, trimethylamin, as well as 
saprin and putrescin, are practically non-poisonous. 

Methylguanidin (C 2 H.N 3 ) is said to have been found in 
cholera cultures, and it occurs in some putrefying mixtures. 
It is a poisonous substance, which causes dilatation of the 
pupil, increased frequency of respiration, paralysis, and con- 
vulsions. Mydalein causes a rise of body temperature, as well 
as dilatation of the pupil, paralysis, and convulsions, its main 
action being similar to that of methylguanidin. 



74 INFECTION 

From infected cheese and cream a substance has been 
isolated called tyrotoxicon, which produces vertigo, nausea, 
and vomiting, with numbness, rigors, and prostration. Mytilo- 
toxin was isolated from the sea mussel (mytilus edulis), 
which caused an outbreak of poisoning in Bremerhaven. It 
acts like curare in poisoning the nerve endings of muscle. 

Peptotoxin, supposed to be formed by pepsin; typhotoxin, 
supposed to be produced by the typhoid bacillus; tetanin and 
tetanotoxin, supposed to be produced by the tetanus bacillus, 
have not been isolated. 

Although but few of the substances named have a definite 
physiological action, there are no doubt others not yet isolated 
which produce the symptoms observed in putrefactive poison- 
ing, these symptoms being mainly referable to the gastroin- 
testinal tract and to the nervous system. 

Products of Pathogenic Bacteria; Toxins of Disease. — The 
chief poisons which produce the symptoms in bacterial disease 
do not belong to any of the classes previously described. They 
are not organic acids, nor are they alkaloidal in nature. The 
poisons may be divided into two classes : 

(i) Intracellular and extracellular poisons (toxins). 

(2) Products of the digestion by the bacterium of proteid 
substances: viz., albumoses and certain by-products. 

Some of these poisons may perhaps be correctly described 
as ferments, but they have not the same properties as the 
digestive ferments. The chemical nature of a ferment can 
only be expressed by the character of the work that it 
performs. It may act in infinitesimal quantities, and it causes 
a transformation in the substances on which it acts. In the 
case of the digestive ferments, the result is to make the 
substances more soluble. Thus both pepsin and trypsin 
digest proteids with the formation of albumoses and peptone; 
in the case of trypsin, a further breaking up taking place 
into leucin and tyrosin. In the case of the diastatic ferments, 
insoluble starch is transformed into different kinds of dextrin, 
and into maltose. 

This, however, is not the only manner in which proteids 



PRODUCTS OF PATHOGENIC BACTERIA 75 

and carbohydrates may be affected by ferments. Albumoses, 
during their absorption into the blood stream, are retrans- 
formed into the proteids of the body. Maltose, in the process 
of its absorption, is transformed into dextrose, and although 
these changes are associated with cell action, yet it is probable 
that the actual change is brought about by ferment action. 

Other ferments exist which transform the physical condition 
of a body, possibly its chemical constitution as well. Thus 
rennin causes the coagulation of milk; that is, precipitates 
the caseinogen of milk in the form of casein. Myosin is, in 
a similar way, formed in dead muscle from myosinogen. 
Fibrin is formed from the blood proteids partly by ferment 
action. Besides, therefore, the digestive ferments, the exist- 
ence of coagulating ferments must be recognized, and both 
of these are the excretory products of cell activity. 

Digestive ferments are sensitive to the action of tempera- 
ture and moisture. They do not act unless water is present. 
They act best at a temperature of about 37° S. The vitality 
of most is affected by a rise of temperature, and the activity 
of most is destroyed at a temperature of 6o° C, or slightly 
over, although, in this respect, they show a varying resistance. 

Ferment action going on in a glass vessel ceases after a 
time, even though active ferment is still present, and there 
are still substances to be acted upon. This effect is usually 
ascribed to the action of the ferment being checked by the 
accumulation of the products of digestion. This may not 
oe the whole explanation, but it is a fact that more 
complete digestion occurs if the products are removed during 
the process by dialysis. 

One feature of ferments, which is of importance, is their 
sensitiveness to manipulation. They keep best in a drv 
condition, but, after keeping, their activity is found diminished 
If kept in solution the deterioration is much more marked; as 
also when t \posed for long to the action of strong alcohol or 
other precipitating agents. 

This sensitiveness to external conditions is also possessed 
by some of the bacterial toxins. Others, again, are very 
resistant. In some of their properties bacterial toxins 



7 6 INFECTION 

resemble ferments, but, in the present stage of knowledge, 
the term ferment is not correctly applied to most of the 
poisons to be considered. Digestive ferments, both diastatic 
and proteolytic, have been obtained from bacteria. These 
have been found to possess the same general properties as 
other similar ferments. The diastatic action of pathogenic 
bacteria is but of slight importance in disease; the proteolytic 
action is of more importance. 

The action of bacteria, however, causes a greater break- 
ing-up of the proteid molecule than the digestive ferments. 
Thus, pepsin does not transform proteids beyond the stage 
of peptone. Trypsin produces only a small amount of leucin 
and tyrosin, which may be considered the final stage in the 
digestion. With the proteolytic digestion by bacteria, not 
only are albumoses formed, but, in some cases, organic acids, 
gases (carbonic acid and hydrogen), aromatic bodies, such as 
mdol and skatol, while a few produce complex nitrogenous, but 
non-proteid, substances. 

The chief poisons of bacteria are the intracellular and extra- 
cellular poisons, which do not belong to the digestive group 
of ferments, and to which the term toxin is most conveniently 
limited. In some instances these toxins alone are produced 
by a micro-organism; in others the bacterium produces this 
poison as well as the digestive poisons; while, in still others, 
the digestive poisons are the chief ones found. There are, 
besides, other substances produced by bacteria, which are only 
slightly toxic, but which are important in relation to the 
formation of antitoxin in the animal body. 

There are therefore five chief groups of bacterial products : 

(t) Poisons produced by the digestive or the destructive 
action of bacteria on proteids. 

Typical examples of these are the poisons of the bacillus 
anthracis and of the pus cocci, with the exception of the 
streptococcus. 

(2) Poisons which are the result of the digestive or destruc- 
tive action of bacteria on proteids, formed in the same medium 
as an execretion (the toxin) of the bacterium. 

The bacillus diphtherias is the best example of this. A 



POISONS IN DIPH THERIA 7 7 

similar combination of poisons is found in snake venom, in 
abrin and ricin. 

(3) Poisons which are only excretions, such as those pro- 
duced by the tetanus bacillus. 

(4) Poisons which are typically intracellular, but are also 
excretory. 

Such are the poisons produced by the typhoid bacillus, the 
bacillus coli communis, the bacillus enteritidis (Gaertner), and 
the cholera vibrio. 

(5) Non-toxic, or slightly toxic elements, which arc im- 
portant in the formation of antitoxin. 

Products of Individual Pathogenic Bacteria. 

Bacillus Anthracis. — If the anthrax bacillus be grown in 
ordinary peptone broth, and removed after several weeks' in- 
cubation by filtration, the broth is found to possess practically 
no toxicity. If. on the other hand, it is grown in broth which 
does not contain peptones, but contains a proteid, such as alkali- 
albumin or serum, capable of being digested, after removal of 
the bacteria, the filtrate is found to contain poisonous sub- 
stances. These are of two kinds : first, the albumoses, and 
secondly, nitrogenous bodies, non-proteid in nature and of a 
resinous consistency. The albumoses give the chemical reac- 
tions of the similar bodies produced in peptic and pancreatic di- 
gestion. The nitrogenous body is alkaline, and contains carbon, 
hydrogen, nitrogen, and sulphur, and forms a very loose com- 
bination with acids. A gold or platinum salt is not formed. 
Both the albumoses and the nitrogenous body (which I have 
elsewhere called provisionally an "alkaloid") have a toxic 
action, that of the latter being more powerful than that of 
the albumoses. Injection of the albumoses into animals 
causes a rise of body temperature and death, the rapidity of 
which is proportional to the dose (Figs. 29 and 30). It also 
produces in rodents diminished coagulability of the blood, 
which is well marked. This is one of the features of the action 
of peptic albumoses in dogs, but not in rodents. The nitrog- 
enous body is an intense local irritant when injected under 
the skin, producing a great amount of edema, but no obvious 



7* 



INFECTION 



necrosis. It does not produce fever, but causes coma and 
rapid death. 

There are no specific symptoms in anthrax; no special af- 
fection of the nervous system or other part. The poison is 
found to cause no degeneration of the central nervous system 
or the nerves, but the albumoses produce a fatty degenera- 
tion of the cardiac muscle, which is a common feature of 



F. 

70S 1 

lot 

1o5 

tor 

100 



Hours under Observation as regards Bodily Temperature 

during Xhr.ee Days; One Day being antecedent to 

Experiment. 



Day before 
Experiment, in 

Hours, 
r 2 2 2(16 hours) 



Day of 
Experiment, in 

Hours. 
2 222(16 hours) 




Second Day 

ill Hours. 

2 2 2 2(16 hoars) 



C. 
o 
40 S 

39' 9* 

39-4° 

38 8° 

38 3° 

31 7° 

372° 



Fig. 29. — Chart showing the effect on the body temperature of the guinea- 
pig by the subcutaneous injection of anthrax albumoses and of peptic albu- 
moses — a, time of injection of anthrax albumoses; b, time of injection of 
peptic albumoses. 

Upper Thick Line.— Temperature of a guinea-pig weighing 430 grams, injected sub- 

cutaneously with o 09 gram anthrax albumoses, unhealed. Dose per kilo, of body- 
_ weight. 0.2 gram. 
Middle Thin Line. — Temperature of a guinea-pig weighing 440 grams, injected with 

0.09 gram anthrax albumoses, boiled in solution for thirty seconds. Dose per kilo. 

of body-weight. 0.2 gram. 
Lower Broken Line. — Temperature of a guinea-pig weighing 460 grams, injected with 

0.09 gram peptic albumoses, unheated. Dose per kilo, of body- weight. 0.195 gram. 
No local edema; no general symptoms, except fever, in any of the guinea-pigs. 

the prolonged action of the poisons produced by bacterial 
digestion. 

The same poisons formed artificially in, and separated from, 
the bacterial culture, are found in the blood and spleen of 
animals (guinea-pigs and sheep), as well as of man, dead of 
the disease. The results of the analysis of the tissues in a 
full-grown sheep dead of anthrax are given in the following 
table : 



POISONS IN DIPHTHERIA 



79 



Sheep inoculated subcutaneously 
with a virulent Anthrax Culture. 


Albumoses. 


Alkaloid. 


From Local Lesion .... 

From Spleen 

From Blood 


0.167 

0.191 

/Chieflv deuteroA Aee 
\ albumose / u -4d5 

grm. 0.813 


O.1346 
I.2080 
O.6430 




grm. 1.9656 



There is no evidence of any amount of toxic excretion of 
the bacillus. Darmier, by using a large quantity of the bacilli, 
separated a toxin, which appears to be one of the intracellular 
poisons. Small doses produce wasting and death, and immu- 
nity may be produced by the toxin. The fact remains, how- 
ever, that the amount of this toxin present is in great contrast 
to the other cases, such as diphtheria and tetanus, where there 
is a large amount of a similar poison excreted. The symp- 
toms in anthrax are mainly to be ascribed to the products of 
the breaking-up of the proteid molecule by the digestive action 
of the bacillus. 



Bacillus diphtheria. — If the diphtheria bacillus is grown in 
broth, unlike the anthrax bacillus, a powerful toxin is found in 
the liquid after the organisms are removed by nitration. This 
poison is referred to as the diphtheria toxin, or sometimes as 
the broth toxin. In addition to this, however, the diphtheria 
bacillus digests proteids, as, when grown in a solution contain- 
ing alkali-albumin or serum, it is found that a large quantity 
of albumoses is formed, together with an acid body; the 
solution, in addition to these, containing some of the toxin 
formed in broth. 

Attempts have been made to isolate the toxin from the 
broth. Ronx, in his first experiments, precipitated it by means 
of calcium phosphate, using Briicke's method for the separation 
of pepsin. He obtained a precipitate which was free of pep- 
tone, and which consisted chiefly of calcium phosphate. It 
was, however, highly toxic, acting in infinitesimal doses. 



8o 



INFECTION 






The action of the broth toxin is very characteristic. It 
is highly poisonous, and even less than o.oi c. c injected sub- 




POISONS IN DIPHTHERIA 



81 



cutaneously will kill a guinea-pig weighing 200 grams. The 
albumoses are less toxic than the toxin. The effect of the 
toxin can be removed from the solution containing the albu- 
moses, either by precipitating by means of alcohol, and keeping 
the precipitate under alcohol for a long time, or by keeping the 
mixture at a temperature of 6o° C. for a few minutes. The 
toxin is not a proteolytic ferment, as it will not digest proteid 
substances exposed to its action. It is, therefore, probably 
not the agent in the formation of the albumoses, which may 
be looked upon as due to the direct action of the micro- 
organism. 

In the actual disease, as it occurs in man. the toxin is 
found mainly in the false membrane, but it is also present in 
the spleen and blood. Albumoses are practically absent from 
the membrane, or exist in only very small quantity. They are 
found in the blood and most abundantly in the spleen, nearly 
t gram of the dried and purified product having been 
obtained from the spleen in some cases, as shown in the follow- 
ing table : 



No. OF 




Albumoses in Grams. 


Alcoholic 
Extract. 


Case. 




Blood and 
Spleen. 


Blood only. 


Spleen only. 


Blood and 
Spleen. 


1 


Larynx. 


O.974 






O.271 


3 


Tonsils. 


0.5955 








4 


Pharynx and 
larynx. 




O.149 




0.107 
(Blood only.) 


5 


Pharynx and 
larynx. 


O.805 


O.450 


0.355 


o.455 


6 


Xose and 
pharynx. 




Trace. 


0.7I5 





Physiological Action. — The toxin and the albumoses have 
a similar action, although that of the albumoses is much weaker 
than that of the toxin. They affect the body temperature, 
the weight, the respiration, the heart, and both the central and 
peripheral nervous systems. 



82 



INFECTION 



The results obtained by an injection of a mixture of albu- 
moses and toxin imitate the combined action of the poisons 
as they exist in the body. In the following table are shown 
the results of injection of the mixed toxin obtained from the 
tissues of patients dead of diphtheria. 



Intravenous Injection in Rabbits of Mixed Diphtheria Albumoses and 
Toxin Obtained from Cases in Man. — Multiple Doses. 



Weight of Rabbit 
in Grams. 


No. of Doses. 


Total Dose per kilo. 

of Body Weight 

in Grains. 


Death in 


Paralysis in 


IIOO 


2 


O.136 


7 Days. 


2 Days. 


1970 


2 


O.I53 


11 " 


6 " 


970 


3 


O.I57 


10 " 


7 " 


1565 


2 


O. IOO 


Killed in 24 
days. 


20 " 


1200 


2 


O.083 


Recovery in 
54 days. 


8 " 



Table of Loss of Weight. 



Original 

Weight in 

Grams. 


Weight at 
Death. 


Proportional 
Loss of 
Weight. 


Death in 


Fever 
Period. 


Dose of Al- 
bumoses per 
kilo of Kody 
Weight. 


I IOO 
1970 

970 


970 
1520 

530 


X 


7 Days. 

11 " 
10 " 


7 Days. 
1 Day. 
6 Days. 


O.136 
O.I53 
O.I57 



The effect on temperature is more marked with the albumoses 
than it is with the toxin, and repeated intravenous injections 
of the albumoses in rabbits frequently produce a rise of tem- 
perature lasting several days after the injections are stopped. 
The toxin also produces a rise of temperature, which, however, 
is very irregular in its course. 

In one experiment 2 c. c. of artificially prepared broth toxin 
was injected into the marginal vein of the ear of the rabbit. 



POISOXS IX DIPHTHERIA 



83 



This was followed by some rise of temperature on the same 
day, and a rapid fall to about 96° F. on the following day, 
ending in death (Fig. 31). When 5 c. c. of the same mixture 
was given, there was a great rise of temperature, followed by 
the death of the animal in shorter time than in the first 
experiment (Fig. 31). 

The diphtheria poisons, besides producing rise of tempera- 
ture, may cause a fall of body temperature. In one experiment 





Hour u Dav 








1 




10 12 2 4 6 8 


10 12 2 4 6 8 


10 12 2 4 6 5 


TO 





105 


104 


— - " '"— — ■ 







* i 


..... , i i -. ■ 


' - *r 


±i#Ni 


~H ! ! HH~ 


-•- 


->-^*«^f-: i Died du 


ring n ght 


j j | 



703 


_|jrr. 


** Vs — Weak in 


A _:_:_;,._- j„, .. 




i-i-4- 


102 


,.!,_= 1 :...:. ..,:..! i L. 


X hind legs 


_ 1 ,. .,.,_]. . 


1 | | ""i - "i "1" 


.. ,..,_ 




..._ V. ; 


! ._ . L.. 






wf 


t Injection. R.M.V. 


.. ;...;._ : _.|--~ 


.J J_|, 


. Y injection. H M.Vl_ 







WO 


_.. „;2 ccm 


rdxr: 


-■-:-'- 


. l \,\J5ccn 


'-_- ^ _..-= l. 


~\ |-|-|-i-t- 




99° 


.-...'_,_ -„;__=...; __;... 


:::1: 


_| — : — : — 


~1 — 1 — |~"l — ' — 


_,. ........ 


'; | | J i |" 


"!~:T 


98° 


--:--- -• : - : ■■■■"■ - 


:: ; 1: :.q: 


_ j 


~H-j4-i |- 


'-■-f- 


97° 


j } . ] { f 1 | | | ._ 


.:... ; jJIpI^ 


, | 1 | | I § | |_.j_ 


.. !....! ....|_J._[_|. 


.L..j 


Qft° 


uit:l400G - 


-\"Y\~\^Dyinq'" "\" 


woo g: ~ ": , 


..;-.. j....|._| ....;....;.. 


... r 



Fig. 31, — Two curves showing the effect on the body temperature in the 
rabbit from the intravenous injection of diphtheria toxin and albumose, 
prepared by growing the bacillus in a solution of alkali-albumin in broth 
(without peptone) for 27 days at 2>7° C. The left curve shows the effect 
of the injection of 2 c. c. The temperature rose slightly on the day of 
injection but dropped suddenly on the following day at the onset of paral- 
ysis. The curve on the right shows the effect of 5 c. c. of the same liquid. 
The temperature rose gradually and the animal died during the night. 

0.2 gram of a dried mixture of the two poisons was injected 
into the marginal vein of the ear of a rabbit. There was 
scarcely any rise of body temperature, but the next morning 
the temperature had fallen 3° C, and the second injection of a 
small dose still further increased the depression of temperature, 
the animal dying in twenty-four hours. 

Heating the mixture of diphtheria toxin almost constantly 
causes a fall of body temperature when injected. Five c. c. 
of broth toxin, which had been kept at 6o° C. for one 
hour, produced a fall of temperature, which was followed by 



8 4 



INFECTION 



a rise to the normal, and 
recovery. In another ex- 
periment, the same dose of 
the same toxin was heated 
for ten minutes at 6o° C, 
and, after injection, pro- 
duced a continuous, but 
gradual, fall of tempera- 
ture up to the time of 
death on the fifth day of 
experiment (Fig. 32). A 
similar dose of the same 
toxin, unheated, produced 
a rise of temperature, not 
a fall (Fig. 32). 

The effect on the body- 
zveight of these poisons is 
to produce a gradual loss, 
which is very great if the 
animal lives a week or ten 
days (Table, p. 82). The 
loss of body- weight is not 
solely due to the dimin- 
ished quantity of food 
taken, but to some change 
in nutrition produced by 
the poison. It is more 
marked in the case of the 
diphtheria poison than in 
that of most of the other 
bacterial poisons, but a 
similar loss of weight ac- 
companies the slow action 
of snake venom and of 
abrin (p. 89). 

The effect on respira- 
tion is well marked, both in 
rodents and in themonkey. 
A rabbit injected with the 



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86 INFECTION 

diphtheria poison shows, towards the end of its action, attacks 
of dyspnea or irregular onset, lasting but a short time, and fol- 
lowed by very rapid shallow breathing. These respiratory at- 
tacks occur usually just before death. In the monkey the effect 
on respiration is seen chiefly in an increased rapidity. In an ex- 
periment in which two doses of 0.3 gram of diphtheria albu- 
moses were injected intravenously into a monkey, there was 
some irregularity in the temperature until the ninth day of ex- 
periment (Fig. 33). The change in the body temperature was 
not nearly so marked as that of the respirations. With the first 
injection the respirations rose to nearly 80 a minute, and this 
increased rapidity, though not so marked, lasted until about 
the ninth day. Three hours after the second injection motor 
palsy appeared, and in seven hours there was complete motor 
and sensory palsy of the limbs and trunk, with loss of knee- 
jerks and skin reflex. There was no loss of consciousness. 
This condition lasted twenty- four hours, the knee-jerks being 
the last to be recovered. 

The effect on the nervous system is partly shown in the 
experiment just quoted. Although, in the rabbit, the diph- 
therial poison has no effect on the spinal cord, yet, in the 
monkey, it can produce complete motor and sensory paralysis 
by affecting this part; and, in man, diphtheria palsy is some- 
times associated with degenerative changes in the cells of the 
spinal cord; and in some cases, of death from acute diphtheria, 
an excessive pigmentation of the cells of the anterior horn 
is observed. There is no evidence of affection of the brain in 
any animal by the poison. 

The chief effect of the poison, however, in man and animals, 
is on the peripheral nerves. In experimental diphtheria in 
rodents, paralysis, slight in extent, sometimes local, some- 
times shown only by a general weakness, is constantly ob- 
served (Fig. 34), and this paralysis is dependent on a wide- 
spread but varying degeneration of the nerves, both sensory 
and motor. The degeneration is seen to be at first a breaking- 
up of the myelin sheath, with its subsequent attenuation and 
disappearance. It may go no further than this, but usually 
the axis cylinder becomes attenuated, and finally ruptured. 



POISONS IN DIPHTHERIA 



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86 INFECTION 

in which case the nerve fiber degenerates to the periphery. 
The nerves most frequently affected are not the large trunks, 
but the small intramuscular branches and the small branches 
of the sensory nerves. The sympathetic nerve fibers may be 
affected, but the vagus was in no case found to be degenerated. 

The effect on the heart, which is so prominent a symptom 
in human diphtheria, is shown in experimental diphtheria 
by degeneration of the muscle fibers, which, in the early 
stage, become granular, and, in the later stage, fatty, losing 
their striation and nuclei. 

The effect on the kidney varies considerably in different 
animals. In man, in the acute disease, and always in very 
severe cases, there may be suppression of the renal secretion, 
the exact causation of which is not known. Occasionally, in 
man, fatty degeneration of the renal cortex follows diphtheria. 
In the rabbit and guinea-pig this does not occur, but it occurs, 
in some cases, in the cat. 

In the rabbit the diphtheria poison may produce fatty de- 
generation of the liver; in the guinea-pig this does not occur, 
but one of the characteristic actions of the bacillus in the 
guinea-pig is the production of double pleural effusion, which 
does not contain the bacilli. 

The other effects of the diphtherial poison will be discussed 
when antitoxins are considered, as well as the nature of the 
poison, in so far as it can be discussed (Chapter VI.). 

Snake Venom; Abrin, Ricin, Robin. — It is necessary here 
to consider certain poisons allied to the bacterial toxins, 
which are produced in one case by the activity of an animal 
cell (snake venom) ; in the other cases by the activity of the 
cells of growing plants, as in the seeds of the abrus pre- 
catorius, or prayer-bead; the seeds of the castor-oil plant (ri- 
cinus communis), and of the robinia pseudacacia. 

Investigation of these poisons has thrown great light on 
the nature of bacterial poisons, and in the main it may be 
said that they show two kinds of poisons, one belonging to the 
class of digestive products; the other an excretory product, 
which corresponds to what has been called above the bacterial 



SXAKE VENOM AND ABRIX 89 

toxin. Thus, chemically, snake venom contains proteids 
of the nature of globulin and albumose. The poison of 
the viperine snakes contains two proteid bodies, the glob- 
ulin and the albumose, both of which are poisonous, and 
each of which appears to have a distinctive action — the 
globulin acting more particularly on the blood, and the al- 
bumose on the nervous system. If the globulin be precipi- 
tated from its solution by heating it to its temperature of 
coagulation, its activity is destroyed, but the toxic properties 
of the albumose are still present, although somewhat impaired. 
Cobra venom does not contain so much globulin as that of 
the viperine snakes, so that heating its solution to the tem- 
perature at which the globulin is coagulated does not 
greatly diminish the toxicity of the venom, and it requires 
the solution to be boiled for a short time before the poisonous 
action is destroyed. 

Abrin. — The seeds of the abrus contain two proteid sub- 
stances, globulin and albumose, both of which are poisonous, 
and both of which produce similar symptoms. The product 
which has been obtained from the seeds and called abrin 
is a mixture of these two substances in varying propor- 
tion. The physiological effect of this substance is, first, that 
of a great local irritant, producing intense conjunctivitis when 
applied to the eye, and causing edema and necrosis of 
tissue when injected subcutaneously. Its general effect is 
that of lowering the body temperature: in pigeons, which 
have naturally a high temperature, the fall of temperature 
may be more than 12° C. (Fig. 35). It also produces a fall 
of temperature in the cat and the rabbit (Fig. 36). The 
number of respirations is increased in some cases; in others 
is diminished. Subcutaneously injected, abrin produces 
diarrhea, which is commonly bloody, and is associated with the 
signs of a hemorrhagic gastro-enteritis, there being great 
inflammation of the mucous membrane of the intestine, and 
especially of the adenoid patches. The symptoms do not arise 
until some time after the injection; that is, there is a period 
of incubation. 

The abrus poisons are very sensitive to heat, the action 



9° 



INFECTION 

1 1% 2 2% 3 3% 4 4h 5 5 T/ 2 6 hours 



Time after Inoculatjon '/< 
Respirations Temp 
per minute F. 
108° 

107° 

106 c 
50 105° 

40 J04° 

30 103° 

20 102 c 

10 Wf 

100° 

Fig. 35. — Showing effect of abrus-albumose on temperature and respira- 
tions of the pigeon. Temperature taken in rectum every half-hour. 
Dotted line, respiration ; thick line, temperature. 

A pigeon, weighing 335 grams, was given hypodermically a dose of 20 mgms. albu- 
mose, equal to 60 mgms. per kilo, of body-weight. In 4^ hours the animal began to 
show symptoms of poisoning, and died in about 6 hours or rather longer. The tem- 
perature began to fall from the first, and with a few rises continued to fall until the 
animal was nearly dead, when the observations were ceased. The curve of 4 the 
number of respirations per minute follows very closely the temperature curve. 



Inoculation I 


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Fig, 36, — Showing the effect of the intravenous injection 
in the rabbit of 50 mgms. of abrin. Soon after the injec- 
tion there was a rapid and continuous fall of temperature 
till death. 



RICIK 91 

of the globulin being completely destroyed by the momentary 
raising of the temperature of its solution to 75° or 8o°C; 
that of the albumose is destroyed at a rather higher tempera- 
ture, 85° C. 

Not only by its , general effects, that is, by its period of 
incubation and by the definite symptoms produced, does the 
abrus poison reproduce the features of an infective disease; but, 
like some of the bacterial poisons, as will be seen, it produces 
an antitoxin which is specific in its action (Chapter VI.). 

Ricin. — In its general action ricin resembles abrin, but 
it is a more powerful poison. By intravenous injection, 0.03 
mgm. per kilo, of body weight is fatal to rabbits (Kobert). 
Y\ nen given by the alimentary tract it may also be fatal, but 
about a hundred times the intravenous dose is requisite, 
and Kobert calculated that, by the digestive tract, 0.18 
gram would be fatal to an adult man. Guinea-pigs are 
very susceptible to the poison, white mice less so; and 
Ehrlich calculated that 1 gram of ricin would kill a 
million and a half guinea-pigs, so that the toxicity of the 
substance, although not so high as that of the poison of 
some snakes and the diphtheria toxin, is still very con- 
siderable (p. 108). Subcutaneously injected, ricin produces, 
like abrin. diarrhea and general prostration, and it also 
gives rise, in the animal body, to an antitoxin, which is 
specific, but differs from anti-abrin. The activity of ricin is 
as sensitive to heat as abrin. Robin is a poison similar to 
ricin and abrin. 

There are other poisons in the animal kingdom which are 
closely related to those which have been just discussed. The 
poison of some spiders has been shown by Kobert to be proteid 
in nature, their activity being destroyed by heat. The blood 
of muraenidae (murena, eel, conger) was shown by Mosso to 
be poisonous. Lupin seeds also contain a poison of a similar 
nature. 

Bacillus tctani. — The tetanus bacillus, when grown in 
broth, neutral or slightly alkaline, in the absence of oxygen 
and in the presence of a small percentage of sugar, forms a 



9 2 INFECTION 

powerful toxin, which has a characteristic action. Guinea- 
pigs are highly susceptible to the poison; mice less so, and 
rabbits still less. When injected subcutaneously it produces 
symptoms, after a period of incubation of greater or less 
duration. The symptoms are mainly confined to the produc- 
tion of tetanic spasms, which are first observed in the muscles 
at the site of inoculation, and subsequently spread all over 
the body. The spasms are both tonic and clonic, and are 
readily excited by external influences, such as pinching the 
skin. During one of these attacks of spasms the animal 
dies. A rise of body temperature, or an irregularity in the 
body temperature, is also a result of the injection of the 
toxin. 

This poison, which in its general chemical characteristics 
resembles the diphtheria toxin, is readily affected by heat. 
It is destroyed by keeping the solution at 65° C. for a few 
minutes, and at 6o° C. for twenty minutes, while at lower 
temperatures it requires a longer exposure to affect its 
vitality. Drying preserves the activity of the toxin. It is 
very susceptible to the action of light and of oxygen, and a 
solution of toxin from these causes soon loses its power, and 
may become practically inert. 

The poison directly combines with the cell elements of 
the central nervous system, and, mainly, with the motor cells 
of the spinal cord, and, to a less extent, of the brain. It 
appears to have no direct action on the peripheral nerves or 
their endings. There is no free poison in the central nervous 
system, but, in some cases, there is evidence of its presence in 
the blood and organs. 

The tetanus bacillus has some digestive action, as is seen 
in its slow 7 liquefaction of gelatin, but this slight digestion 
appears to have no relation to the formation of toxin, and 
is much less marked than is the case with the diphtheria 
bacillus. 

From the organs of persons dead of tetanus no poison- 
ous substances may be obtained. From the central nervous 
system no free poison can be extracted, owing, doubtless, to 
the fact that the toxin combines with the cell elements,. 



POISONS IN TETANUS 93 

But with the heart blood, in one case, Kitasato found that 
injection of the serum gave rise to the characteristic spasms of 
tetanus. In an extended examination of the spleen and blood 
in several cases of tetanus, no poison corresponding to the 
toxin was found, possibly because the prolonged manipula- 
tion with alcohol and exposure to light may have destroyed 
it, but two classes of products were separated. Albumoses 
were present in the spleen and blood, and gave rise, on 
injection, to fever, but not to tetanic spasms. On the other 
hand, certain non-proteid bodies were extracted, some soluble 
in alcohol and some in ether, and, in two experiments, the 
injection of the latter gave rise to definite tetanic spasms, 
with rapid death in one case and recovery in the other. In 
these cases spasms came on in a few minutes, and there was 
no period of incubation, such as is seen in the action of the 
toxin. It may be that these non-proteid bodies are the 
immediate agents in producing the spasms, the chief poison 
being the toxin which is formed in peptone broth, or in 
solutions containing no proteid matter. The toxicity of the 
poison is very great; one-twentieth of a milligram is fatal to a 
mouse. 

Contrasting the chemical products of the diphtheria 
bacillus and the tetanus bacillus, it is seen that in both 
there is a toxin formed, which is the chief agent in pro- 
ducing the symptoms of the disease; that in both there is 
evidence of a digestive action of the bacillus, and of the 
formation of certain end products; but whereas, in the case 
of diphtheria, the albumoses produce fever, with paralysis 
and some degree of nerve degeneration, in the case of tetanus 
they appear to have no special action except that of producing 
fever. One of the end products in the case of the diphtheria 
bacillus is an organic acid, which produces a slight degenera- 
tion of the nerves. There is evidence in the case of tetanus 
that some, at least, of the end products are capable of giving 
rise to tetanic spasms. 

Bacillus typhosus. Bacillus coli communis, and Bacillus 
enteritidis (Gaertner). — These three bacilli may be grouped 



9 4 INFECTION 

together in the consideration of their poisons, as not only 
are they closely related morphologically, but the poisons they 
produce are of a similar nature. 

They have a very slight digestive action, the typhoid 
bacillus least of all, and the poisons they form are, to some 
extent, excreted, but are mainly found in the bodies of the 
bacilli. 

If a virulent typhoid bacillus be grown in broth, and, 
after a period of two or three weeks or longer, the bacillus 
be removed by nitration, the filtrate is found to have a 
definite, but slight, toxicity. If, after growing even a shorter 
time, say for seven clays, the bacillus be not filtered off, but 
be killed by chloroform, it is found that the toxicity of the 
liquid, when injected, is much greater than if the bacillus 
be removed. It is still more increased by breaking up the 
bodies of the bacilli by prolonged exposure to a temperature 
of 6o° C, by drying the broth, and grinding the residue to a 
powder, or by separating the bacilli by centrifugalization, 
drying them and grinding to a powder. The bodies of the 
bacilli are, therefore, necessary in order to obtain a highly toxic 
product from artificial cultures, and the dead bacilli may be 
boiled for five minutes, not only without destroying the toxicity 
of the poison, but with the result of actually bringing out its 
effects. This effect of heat on the typhoid toxin is in great 
contrast to the effect of even moderate temperatures on the 
toxins of diphtheria and tetanus, and the poison is also con- 
trasted with these by the fact that, in any artificial culture, it 
exists mainly in the bodies of the bacilli, and is excreted into 
the liquid only to a slight extent. 

The digestive action of the typhoid bacillus, when it is 
grown in a liquid medium containing alkali-albumin or serum, 
is very slight. Some albumoses are formed, but in very 
small quantity, even after thirty-two days' culture. This is 
again in great contrast to the digestive action of anthrax and 
of diphtheria. 

The physiological effects produced by the typhoid toxin 
are well marked. They consist, in rabbits, of a great lower- 
ing of the body temperature and in the production of profuse 



POISOXS IX TYPHOID FEVER 



95 
is introduced 



mucous diarrhea, in whatever way the toxin 
into the body, except by the mouth. If the poison is given 
in a small dose intravenously, it may produce an initial fall 
of temperature, but no diarrhea, and the chief symptom 
observed is wasting, which steadily progresses until death. 
In these cases there is no obvious gross change in any of 
the organs after death, but, on staining with osmic acid, the 









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780 
760 
740 
720 
700 
630 
660 
640 
620 



Fig. 2>7- — The effect of the typhoid toxin on the temperature and weight 
of the rabbit. The liquid injected was a i3-days'-old culture of the virulent 
bacillus in peptone broth. The bacilli were then killed by chloroform, the 
latter evaporated off in vacuo and the mixture of broth and bodies of the 
bacillus injected intravenously. The result is shown as a lowering of the 
body temperature, at first suddenly, afterwards gradually till death. There 
was also a progressive loss of weight. The upper line represents the 
weight, the lower line the temperature. 

heart muscle shows well-marked fatty degeneration of its 
fibers. 

A depression of the body temperature is one of the most 
marked features in the action of the typhoid toxin in rabbits, 
and this depression may continue until death occurs. It is 
seen when a large dose of the poison is injected (Figs. 37 
and 38). In other cases, where the amount of poison in- 
jected is less, there is an initial fall of temperature, followed 
by a rise above the normal, lasting, perhaps, two or three 
days (Fig. 30). With a very small dose of the poison, a 



96 INFECTION 

slight rise of temperature only may be noted. In man, the 
typhoid poison, as obtained from artificial cultures, produces 
a rise of temperature, and not a fall. It has been used 
extensively in antityphoid inoculation, the liquid employed 
being simply the dead bodies of the bacillus from an agar 
culture, or from broth. After injection there is a local 
swelling, with pain, and more or less edema, and, after a 

few hours, there is a rise 
of temperature to 102° C, 
or above, which lasts from 
eighteen to twenty - four 
hours (Fig. 40). 

Sanarelli described def- 
inite changes in the 
Peyer's patches of the in- 
testine as the result of the 
subcutaneous injection of 
the typhoid toxin. These 
changes were swelling, 
congestion, and even su- 
perficial ulceration of the 
Fig. 38.— The effect of the dried ty- n „ trnpQ Tt -11 t_ rp _ 
phoid toxin (intracellular poison). The P atcn CS. It Will De re 
bacilli were killed by heating the cul membered that a subcil- 
ture fluid twice for 10 minutes to 60° 4. n „„^*„ ;„:„„*■:„„ ^-C ^k«-;~ 
C. They were then separated by centri- taneous injection of abrm 
fugalizing, washed with distilled water, produced this effect On the 
and dried over sulphuric acid. The j^-,*™ u uf a ll observer* 
dried bodies (0.02 gram) were ground "destine, Dut aU Observers 
up with a little water and injected in- have not found this change 
travenously. There resulted a sudden • fn intestine with the 
fall of temperature, diarrhea and death m tne mtestine wim me 
in 2% hours. typhoid toxin. 

From the spleen of persons dead of typhoid fever, 
albumoses in fair quantity may be obtained. Thus, in three 
different cases, 0.369 gram, 0.37 gram, 0.652 gram were 
obtained, which gave the chemical reactions characteristic 
of the bodies. Beyond, however, producing a slight rise 
of temperature, the albumoses were found to have but little, 
physiological action. The alcoholic extract of the spleen 
was also without effect. The toxin may, however, be 
extracted from the spleen when the splenic pulp is rubbed 





a.m. 

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POISOXS IX TYPHOID FEVER. 



97 



through wire gauze and filtered, after being treated with 
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Fig. 39. — The effect of the typhoid toxin on the temperature of the rabbit. 
The liquid was a /-days' culture of the bacillus in peptone broth; the 
bacilli were treated as described under Fig. 37 and the mixture of dead 
bacilli and broth injected intravenously. Following the injection there is a 
steady rise of temperature, highest on the following day (107 F.) : the 
animal subsequently recovered. The experiment shows a weaker action 
of the toxin than that in Figs. 37 and 38. 




Fig. 40. — Temperature reaction following the subcutaneous injection of 
typhoid vaccin (1.5 c. c. m.) in a healthy male set. 18. The pyrexia pro- 
duced lasted, with a slight intermission, for 48 hours. The vaccin is a 
mixture of broth and bodies of the bacillus, and the result may be compared 
with the mild action of the toxin in rabbits shown in Fig. 39. 



filtrate into rabbits was found, after a period of incubation, 
to cause a great fall of temperature, with collapse and profuse 



98 INFECTION 

mucoid diarrhea, effects which are precisely similar to those 
produced by the toxin of the typhoid bacillus obtained from 
artificial cultivation. 



So 




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Gaertner's bacillus closely resembles the typhoid bacillus, 
and differs chiefly, in culture, by the fact that it forms gas 
in glucose-gelatin. The character of the poison which it 



POISONS OF THE COLON BACILLUS 



99 



produces is similar to that of the typhoid toxin, namely, that 
it produces a great depression of temperature, with loss of 
weight and diarrhea (Fig. 41). 

It is slightly more active than the typhoid bacillus in its 
digestive effect on proteids, but, unlike the typhoid bacillus, 
when grown in Marmorek's fluid (broth, two parts; serum, one 
part), it sometimes pro- 
duces a partial precipitation 
of the proteid solution in the 
form of a gelatinous clot. 

Bacillus coli communis. — 

The type of action of the 

poison of the bacillus coli 

communis is the same as 

that of the two other bacilli. 

in some cases producing a 

great fall of temperature 

(Fig. 42), and. in others, a 

rise of temperature, with a 

loss of body weight, and, in 

some cases, the production 

of diarrhea. 

T t . Fig. 42. — The effect of the intra- 

mucn greater ex- venous injection of the intracellular 





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tent than the two 
bacilli, bacillus coli 



other 
com- 



mjection 

toxin of the bacillus coli communis in 

a rabbit. The liquid injected was an 

18-days' culture of the virulent bacillus 

munis digests proteids, but in peptone broth, heated to ioo° for 10 

4-u:^ ~(Z~„4r :^ r-4-; 11 t~~. u~u:~a minutes. The toxin caused a rapid fall 
this effect is still far behind of temperature and death in 6 h 5 urs . 

the digestive activity of the 

anthrax or the diphtheria bacillus. When grown in the pres- 
ence of coagulable proteids. such as diluted serum or Marmo- 
rek's fluid, the bacillus coli communis causes the precipitation 
of the proteid in the form of a gelatinous clot. This clotting of 
the proteid solution is of interest in connection with the ex- 
periments of Stillmark. who found that ricin also produces a 
clotting in proteid solutions, especially serum. Stillmark used 
it as an argument in favor of the ferment nature of ricin. 

Heating the dead bodies of the bacillus, suspended in the 
broth culture fluid, increases the toxicitv of the solution, as 



ioo INFECTION 

with the typhoid bacillus and Gaertner's bacillus, but, in the 
case of the bacillus coli communis, it requires a temperature 
of the boiling point of water to effect this. 

Altogether, the mode of action of the toxin of the bacillus 
coli communis is more irregular than that of the poisons of 
the other bacilli, not only as regards the lethal dose, but also 
as regards the irregular kind of fever and after-fever produced. 

Vibrio cholera asiaticce. — The products of the cholera 
vibrio may be divided into the two classes already described, 
namely, the toxin and the products of proteid digestion. 
The toxin is a most powerful poison, and is chiefly intra- 
cellular, although it is also excreted from the body of the 
bacillus. Pfeiffer thought the main poison intracellular, intra- 
peritoneal injections causing collapse and a great lowering of 
the body temperature, and sometimes clonic spasms. The 
excreted poison, examined by Metchnikoff* and Roux, had a 
physiological action like Pfeiffer's toxin. The latter, however, 
found that most of the toxicity was destroyed at 6o° C., but 
other observers have shown that the cholera toxin is not, 
in the main, destroyed, even at ioo° C. 

The action of the cholera toxin in producing collapse and 
a fall of body temperature brings it into close relation, in its 
effects, with the intracellular toxins of the three bacilli last 
considered, namely, the typhoid bacillus, bacillus coli com- 
munis, and Gaertner's bacillus. 

The cholera vibrio also digests proteids, and the albu- 
moses, in the condition in which they are separated, possess 
toxic properties, sometimes to a marked extent (Scholl). 
The digestive action of the cholera vibrio is, as a rule, much 
greater than that of the three bacilli last mentioned. The 
intracellular toxin must, however, be considered, according 
to present knowledge, as the most important poison produced 
by the cholera vibrio. A large dose produces very rapid 
death, and 0.4 c. c. of the filtrate of a broth culture of a viru- 
lent vibrio will kill a guinea-pig weighing 200 grams. 

Bacillus tuberculosis. — The exact nature of the chemical 



TUBERCULIN 



12 15 18 



Rectal: Ten 



P e (P- t J , . r ?s..S..J. 



products of the bacillus tuberculosis is not known, but the 
following facts are not without interest. Koch prepared a 
substance which he called tuberculin, which consisted of a 
glycerin broth culture of the bacterium, in which the bacilli 
had been killed by heat. This liquid is toxic to healthy 
animals. Injected into a healthy calf, or in smaller doses, 
into a healthy man, it causes malaise and a moderate 
degree of fever, the symptoms soon passing off. If, however, 
a much smaller dose be injected into a man or animal, the 
subject of tuberculosis, what is called the tuberculin reaction 
ensues (Fig. 43). Sometimes there is well-marked edema at 
the site of inocu- 
lation, but the 
prominent symp- 
tom is a rise 
of temperature of 
3 C. or more, 
which ensues in 
a few hours, and 
is followed by a 
fall. Besides this 
rise of tempera- 
ture, there is an 
effect on the tu- 
berculous lesion, 
round which in- 
flammation occurs, the lesion itself undergoing necrosis, and 
being, in some instances, destroyed. The effect in tuberculous 
guinea-pigs and in tuberculous human beings is very irregular, 
the most marked results being seen in lupus. 

Koch has described a tuberculin " R." and " O." The 
latter is prepared by grinding up virulent cultures of the 
bacillus, after drying, and treating them with distilled water. 
The first extract is the tuberculin " O." Successive extracts 
of the residue, when more dissolved, were mixed together, 
and called tuberculin " R." Tuberculin " O " resembles the 
original tuberculin; " R," in repeated small doses, is said to 
produce immunity against tuberculin, and against living 





Fig. 43.— Cha: ts of the tuberculin and of the 
mallein reaction, The left curve shows the effect 
of the injection of tuberculin in a tuberculous cow; 
the right curve that of mallein in a horse suffering 
from glanders (Prof. J. McFadyean.) 






102 INFECTION 

tubercle bacilli. At present this statement must be received 
with some caution. It is quite clear, however, that from the 
bodies of the tubercle bacillus can be extracted a substance 
which has a specific action on a tuberculous lesion, although 
this cannot be considered, in the majority of instances, a bene- 
ficial action from the point of view of treatment. 

Tuberculin contains albumoses and non-proteid extractives. 
It is, however, not accurate to describe these albumoses as 
products of the tubercle bacillus, inasmuch as they are 
present in the original broth, and although, when separated 
by the only methods known, which are somewhat crude, the 
albumoses give the tuberculin reaction, yet tuberculin can be 
prepared free from albumoses, as when tubercle bacilli are 
grown in a medium containing a nitrogenous non-proteid 
substance, such as asparagin, instead of peptone. 

It has been considered doubtful whether the tuberculin 
reaction is specific, that is, whether it is the only substance 
which can produce the effect, for it has been found that 
ordinary peptic albumoses, ricin, lactic acid, and even milk, 
give a similar reaction in tuberculous guinea-pigs; and 
Buchner stated that the bodies he called proteins gave the 
reaction. On the other hand, it has been stated that tuber- 
culin reacts in cases other than tuberculosis, such as cancer 
and syphilis. But it is doubtful whether it reacts, in such 
cases, in the small doses which are effectual in cases of 
tuberculous disease. 

There is no evidence, as yet forthcoming, that the tubercle 
bacillus possesses any digestive properties, but other sub- 
stances have been described as due to its activity, which 
may be classed under the heading of nucleo-proteids. Of 
this nature is probably the poison separated by De Giaxa. 
When injected into the veins in large doses, it causes throm- 
bosis in the right heart and the pulmonary artery and 
its branches, the animal dying in asphyxia. Small doses 
cause capillary thrombosis, especially in the liver and king; 
in the lung, catarrh and pneumonia may be found instead of 
infarction, and both the liver and the kidney may be found, 
fatty. Subcutaneously injected, similar results are observed, 



MALLEIN 



103 



although the effect is much slighter. A local lesion produced 
by these injections consists chiefly of leukocytes, which 
undergo caseation and not uncommonly fibrosis. Intra- 
tracheal injection of the poison causes catarrh and pneumonia 
and even nodules, which resemble true tubercles (Boccardi). 
De Giaxa states that rabbits, goats, and horses, treated with 
the poison, give the reaction of tuberculin. 



Bacillus mallei. — A substance called mallein has been 
prepared from this bacillus, which resembles tuberculin in its 
action. The bacillus 
is grown in glycerin 
broth for three or 
four weeks, and, after 
destroying the bacil- 
lus by heat, the liquid 
is filtered and is 
called mallein. One 
c. c. of this liquid, 
injected into a horse 
suffering from glan- 
ders, causes a large 
and painful local 
swelling within 
twenty - four hours 
and a rise of tem- 
perature of over 2 C. 
(Figs. 43 and 44). 
Mallein is used for 
the diagnosis of glanders in animals, and is of great value in 
this respect. 

Buchner extracted from the bodies of certain bacilli, 
namely, those of anthrax and glanders, and the bacillus pro- 
digiosus. certain albuminous bodies which he called proteins. 
These contain nitrogen, and give the general reactions of 
proteids, but are not sufficiently defined to be classed with 
any of the known groups of these substances. Probably they 
correspond to some of the intracellular toxins which have been 
discussed, and it appears hardly necessary to retain the name. 




Fig. 44. — Mallein swelling in horse. 
The figure shows the large swelling in the neek of 
a horse suffering from glanders, which follows the 
subcutaneous injection of a dose of mallein. At the 
same time as the swelling there is a temperature reac- 
tion (Fig. 4 V). (Prof. J. McFadvean.) 



io 4 INFECTION 

General Action of Bacterial Poisons. — Although our knowl- 
edge of the poisons produced by bacteria is, at present, very 
imperfect, yet it is clear that it is by their means that patho- 
genic micro-organisms are capable of producing the effects of 
infective disease. It is by their formation, more or less rapid 
according to the activity and growth of the micro-organism in 
the body, that an infective disease, lasting days, weeks, or 
months, is possible. Any mechanical action due to a large in- 
crease in number of bacteria blocking the vessels, is fortuitous, 
and is a special feature of the process of infection in any disease. 

None of these poisons can, as yet, be defined chemically; 
in none of them is there indication of their chemical constitu- 
tion, and of some, referred to as the " toxins," an ultimate 
analysis has not been made, as is the case also with pepsin, 
diastase, or other ferments. Speaking generally, the poisons 
can only be denned as regards the effect of external conditions 
on them (such as heat, light, oxygen), and as regards their 
physiological action in the animal body. In the preceding 
pages, two groups of these poisons have been made; one 
containing the products of the digestion of proteids by the 
bacterium, which may be called the digestive group of bacterial 
poisons, and the other, in which the poison is either intra- 
bacterial, or is an excretion of the bacterium. This group is 
more toxic than the members of the first group, and resembles, 
in some of its properties, the bodies known as ferments. 

The association of the poisons of both groups with bodies 
of a proteid nature is an important fact, and the association is, 
in most instances, so close that the proteid cannot be separated 
from the toxin. 

General Action. — After injection there is no immediate 
effect of the poison. This is because there is a period of incu- 
bation which is followed by the symptoms peculiar to the action 
of the poison. 

The body temperature may be affected in two ways : either 
in the production of a febrile rise, or of a great depression 
of temperature. 

The poisons produce degeneration of tissues, and a special 



GENERAL ACTION OF BACTERIAL POISONS 



105 



action on the nervous system and the heart. This selective 
affinity of toxins for special organs and parts is a very charac- 
teristic action, and is also observed with non-bacterial poisons. 
Blood destruction, or hemolysis, is another effect of the bacterial 
poisons. 

( 1 ) The products of the first group, the digestive products of 
bacteria, are chiefly the albumoses, which are constantly found 
in the body after death from infective disease, and are excreted 
in the urine. Their mode of formation and relation to normal 
proteolytic digestion are shown in the following table : 



Primary Agent, or Secondary Agent, or 
Primary Infective Agent. Ferment. 


Digestive Products. 


Living cell .... 


Pepsin .... 


f Syntonin. 
1 Hetero-albumose. 
Proteid < Proto-albumose. 

j Deutero-albumose. 
[_ Peptone. 


Living cell .... 


Trypsin .... 


Proteid \ Globulin-like bod >'- 
( Tryptone (Peptone). 
Proteid ( Leucin, tyrosin. 
product I A bitter body. 


Bacillus anthracis . 


Anthrax digestion 


f Hetero-albumose. 

1 Proto-albumose. 
Proteid { De utero-albumose. 

1 Peptone. 
Proteid j Alkaloid (base), 
product ( Leucin, tyrosin. 


Bacillus diphtheriae . 


Diphtheria toxin . 

(Roux and Yersin's 
poison) in mem- 
brane. 


•a ( Hetero-albumose. 

-2 -{ Proto-albumose. 
j 

£ L Deutero-albumose. 

.J f 
■^'5 { Organic acid . 


)£* 

In 
^body. 



106 INFECTION 

In some diseases the toxic albumoses appear to play an 
important role, such as anthrax, diphtheria, and pus infection; 
and similar albumoses, although with a different action, are 
found in abrus seeds and in snake venom. Albumoses, no 
doubt, differ considerably in their toxicity, and, probably, in 
their chemical constitution. The albumoses formed in gastric 
digestion are poisonous when injected into the veins of an 
animal. In the dog they produce great fluidity of the blood 
and a fall of blood pressure. They also produce in other 
animals a considerable rise of body temperature and may cause 
death. This effect of peptic albumoses cannot be ascribed to 
the ferment pepsin which may be present associated with them. 
Pepsin may be more or less completely destroyed by heat, and 
the albumoses still retain their toxic power, although this is 
diminished. 

In the case of anthrax it is quite clear, from the facts 
which have been brought forward, that the albumoses play 
an important part in the disease, and that their action is not 
due to the association of any toxin which may be sepa- 
rated by heat. In other instances, however, there is great 
difficulty in deciding how far the toxicity of the albumoses 
is due to the presence, in association with them, of a toxin 
or excreted product. Thus, in diphtheria, both toxin and 
albumoses are present in quantity. By heat or by alcohol 
the activity of the toxin may be fairly readily destroyed, 
and the albumoses are then found to have a definite action,, 
which is like that of the toxin, only weaker, except that 
it is a more certain fever-producer than the toxin. The 
albumose, separated from toxin, has also been found to 
cause the production of antitoxin in the blood of the 
horse. 

In the case of abrin, a poisonous globulin and albumose are 
present, and both are very sensitive to heat. No toxin has 
been separated from these bodies, although it is possible to 
assume that one is associated with the proteids. Snake venom, 
in which there are also a poisonous globulin and albumose, is 
in the same position as abrin. In many instances, however, 
the bacterium does not appear to have any great digestive 



GEXERAL ACTION OF BACTERIAL POISONS 107 

power, and the chief toxins in the disease appear to be the 
excretion of the micro-organism. 

2. The poisons of the second group are essentially of a 
different nature to those of the first group or class of digestive 
proteids. Several considerations are against the conclusion 
that all these poisons are of a proteid nature. Diphtheria 
poison is as toxic as cobra venom, or as the venom of the 
Australian tiger-snake (hoplocephalus curtus). Roux and 
Yersin obtained the diphtheria toxin from the broth culture 
in such a form that it acted in imponderable doses. Brieger 
and Gohn, by means of precipitation by zinc salts and the 
subsequent decomposition of the zinc salts with carbonic 
acid, obtained a toxic product from diphtheria, causing all 
the characteristic symptoms ; but this product did not give 
any proteid reactions, neither the xantho-proteic nor the 
biuret reaction, so that it may be considered that the 
diphtheria poison is not necessarily associated with a distinct 
proteid. 

It may be that this poison, together with the poison of 
tetanus and the intracellular poisons previously discussed, is 
of a ferment nature. The arguments which may be used in 
this respect are : 

( 1 ) That they act in infinitesimal doses. 

(2) That they act after a period of incubation, and slowly; 
and may produce death after many days by profoundly affect- 
ing the general nutrition. 

( 3 ) That they are sensitive to the action of heat. 

This sensitiveness to the action of heat is, however, not 
universal. On the one hand the toxins of diphtheria and 
tetanus are more sensitive to heat than the digestive ferments; 
but the toxins of the typhoid bacillus, of the B. coli communis. 
of Gaertner's bacillus, and of the cholera vibrio resist for a 
time a temperature of ioo° C. If these poisons are of a 
ferment nature, their physiological action is unlike that of 
any of the other known ferments. They are not digestive 
ferments, in the ordinary sense of the word. Experiments 
made to test the digestive action on ordinary proteids of the 
diphtheria and tetanus toxins have not shown the slightest 



io8 



INFECTION 



indication of digestion. But digestive ferments are not the 
only substances of the kind which are known, and although 
bacterial toxins may themselves have no digestive action, 
yet they may, when combined with the particular tissue they 
affect, produce poisons which are formed in the splitting up 
of bodies contained in the cell. There is some evidence that, 
in the case of tetanus, such a poison, which is not the toxin, 
is present in the body. 

The toxins produced by micro-organisms, though they 
may be related to each other, are not identical. The differ- 
ence is sometimes shown in the special tissues which they 
select for their action, and in the symptoms produced, but 
the most definite test for the toxin is what may be called 
their toxic reaction in the body, which results in the formation 
of substances antagonistic to their action (antitoxins). In 
the case of abrin and ricin, the physiological actions are 
closely similar, ricin acting rather more powerfully than 
abrin : so that, as far as their physiological action goes, if 
these alone were investigated, they might be considered as 
identical substances. But an animal which has been made 
immune to abrin is not immune to ricin, and vice versa 
(Ehrlich), so that the poisons, although they may be related, 
yet are essentially different. Further discussion of this 
subject will be made under the heading of " Immunity " 
(Chapter VI.). 

The following table shows the comparative toxicity of some 
of the substances which have been discussed. The figures 
represent the number of grams of body weight of a rabbit 
or guinea-pig, which will be killed by i gram of dried 
poison : 



Hoplocephalus curtus. 


4,000,000 


Diphtheria toxin 


4,000,000 


Ricin . 


1,500,000 


Psendechis (viper) 


80,000 to 2,000,000 


Pelias berus (adder) . 


250,000 


Anthrax albumoses . 


3,000 


Cholera albumoses 


3,000 



CHAPTER V 

infection — continued 

III. The Infective Process 

In previous chapters the characters of the infective agent and 
of the chemical products of its life processes have been con- 
sidered. The character of the infective process, as it affects 
mainly the human being in individual diseases, will now be 
considered. 

Proof of an Infective Agent being the Cause of Disease. — 
In order to prove that an infective agent is the cause of an 
individual disease, it is necessary to determine the following 
facts, which may be stated as postulates : 

i. The infective agent must be constantly found in the 
disease. 

2. It must be obtained from the lesions of the disease or 
from the blood and tissues in pure culture. 

3. It must reproduce the disease in susceptible animals. 

4. It must be obtained from these animals in pure culture. 

5. The chemical products with an identical physiological 
action must be obtained from artificial cultures of the infec- 
tive agent and from the tissues of man or animals dead of 
the disease. 

6. A specific serum reaction (antitoxic, antimicrobic) is 
to be obtained with the infective agent. 

It is not necessary, in order to demonstrate that a particular 
micro-organism is the cause of a disease, to prove all these 
propositions. In the case of most diseases due to bacteria 
the first four propositions are, as a rule, readily shown, with 

109 



no INFECTION 

the exception that, in some instances, it is impossible to find 
an animal susceptible to the disease. The fifth proposition 
applies mainly to those instances where the chemical products 
of an infective agent have a specific action which is readily 
investigated, such as is the case with the bacillus of diphtheria 
and of tetanus. The specific serum reaction, when obtained 
both from the blood of patients suffering from the disease, 
and from the blood of animals rendered immune by treatment 
with the infective agent or its products, is an additional and 
conclusive proof of the specificity of the infective agent. 

As illustrations, the following examples may be quoted. 

The proof of pus cocci being the cause of suppuration rests 
on the fact that they are constantly found in abscesses, from 
which they may be separated in pure culture. This pure culture 
can reproduce abscesses in animals or a condition of septi- 
cemia, and the cocci can be obtained from these animals in pure 
culture. 

In other instances, evidence of the micro-organism being 
the cause of the disease rests on the same experimental data. 
This is the case with the pneumococcus and pneumonia ; with 
the bacillus anthracis and anthrax; the bacillus mallei and 
glanders ; with the bacillus pestis and plague ; with the bacilli 
of diphtheria and tetanus and the corresponding diseases ; with 
actinomyces and actinomycosis. 

In the case of diphtheria and tetanus, however, there is 
another proof, embodied in the fifth proposition stated above. 
The chemical products present in the bodies of patients dead 
of diphtheria produce a palsy due to nerve degeneration, similar 
to that caused by the products of the bacillus of diphtheria 
which are formed outside the body in culture media. In tet- 
anus, the products of the tetanus bacillus produce the character- 
istic tetanic spasms, although it is not possible to obtain from 
persons dead of the disease, in the majority of instances, any 
poison producing these spasms. 

It is not necessary that the disease produced in animals 
should reproduce the lesions characteristic of the disease in 
man, in order to prove that the micro-organism is the specific 
infective agent. In some instances, such as is the case with 



rROOF OF INFECTION in 

the pus cocci, tuberculosis, actinomycosis, tetanus, and anthrax, 
the lesions of the disease produced in animals are practically 
identical with those occurring in man. In the case of diph- 
theria, it is not always easy to reproduce in animals the 
membrane characteristic of the disease in the human being, 
although this has been done, but the lesion produced by the 
subcutaneous injection of the bacillus is pathologically identical 
with the false membrane, inasmuch as it shows the character- 
istic fibrin exudation and necrosis of the tissues. 

In the case of some diseases, such as cholera and typhoid 
fever, no animals naturally susceptible to the disease are known. 
Both the typhoid bacillus and the cholera vibrio are, as has been 
seen, pathogenic to animals when introduced intraperitoneally 
or subcutaneously. By using alkalies to neutralize the acidity 
of the stomach contents, and opium to quiet peristalsis, Koch 
succeeded in reproducing in pigs the symptoms of cholera, 
ending fatally, by introducing the vibrio into the alimentary 
tract. In previous experiments, choleraic symptoms were 
produced by injecting the organisms directly into the duodenum 
of pigs and rabbits (Nikati and Rietsch). Subsequent experi- 
ments have shown that an intestinal infection occurs in the 
marmot by feeding with the vibrio, and, similarly, very young 
rabbits become infected when the vibrio is added to the milk 
given as food. The symptoms produced are great prostration, 
subnormal temperature, sometimes anuria and cramps, with 
diarrhea. 

Other micro-organisms, such as the spirilla of Finkler- 
Prior, of Deneke, and of Miller, will produce these symptoms. 
But the fact remains that the vibrio, which is found constantly 
associated with cholera, is capable of producing in animals 
an intestinal infection, with the symptoms of the disease. 
Experiments have been performed by workers on themselves. 
Both Emmerich and Pettenkofer swallowed the vibrio, with 
the production of diarrhea, the motions containing the vibrio ; 
serious illness ensued in one case. A worker with the vibrio 
in Hamburg contracted fatal cholera from a cultivation at a 
time when there was no cholera in Germany. That the vibrio 
is the cause of the disease is shown by the results of preventive 



ii 2 INFECTION. 

inoculation against cholera (p. 170), in which the vibrio' is used 
subcutaneously as a prophylactic, and which has resulted in the 
reduction of the mortality ; by the facts already stated ; as well 
as by the specific serum reaction (p. 187). 

The case of typhoid fever is somewhat similar to that of 
cholera, inasmuch as no animal is naturally susceptible to the 
disease, nor, in most animals, is it possible to reproduce the 
intestinal lesions of the disease. Remlinger has produced in 
some rabbits a definite infection of the intestine by giving them 
virulent cultures with their food. Some of the rabbits were not 
infected; after a period of fever, diarrhea, and bodily depres- 
sion, with loss of weight, undergoing complete recovery. 
Others, however, succumbed with the same symptoms, and 
there was found great congestion of the small intestine, the 
contents of which were liquid. Peyer's glands were enlarged, 
and there was some ulceration at the level of the cecum. The 
spleen was greatly enlarged, and the bacillus was obtained in 
pure culture from the organs. In one experiment the animal 
was fed for five days with the typhoid bacillus. On the eighth 
day fever was observed, and there ensued the train of symptoms 
previously mentioned up to the seventeenth day, when the 
animal died. In another experiment seven days after feeding 
the fever began, and the symptoms progressed for twenty days, 
ending in death. Similar results were obtained in rats. The 
blood serum of the infected animals gave the specific typhoid 
reaction (p. 188). Intestinal infection by the typhoid bacillus 
has also been successfully carried out by the method used by 
Koch for the cholera vibrio. The chimpanzee has also been 
successfully infected through the intestines, ulceration being 
produced. Besides these facts, however, the occurrence of the 
typhoid serum reaction with the blood of animals rendered 
immune to the bacillus, as well as in the blood of patients 
suffering from disease, is a proof of the bacillus being the 
cause of the disease in man, inasmuch as this reaction is 
specific. 

In some cases of disease the infective agent has not yet 
been cultivated. This is the case, e. g., with leprosy, relapsing 
fever, and malaria. 



SOURCES OF INFECTION j 13 

The leprosy bacillus shows the characteristic staining 
reaction of the B. tuberculosis which is possessed, to a less 
extent, by the smegma bacillus, by the Timothy grass bacillus, 
and Rabino witch butter bacillus, i. e., the red color of the 
fuchsin taken up by the bacillus is not discharged by mineral 
acids (acid- fast bacilli). The leprosy bacillus, however, has 
not been cultivated, and the inoculation experiments in human 
beings, which must necessarily be scanty, are quite inconclusive. 
The leprosy bacillus is, however, not the same as the bacillus 
tuberculosis : tuberculosis may occur in lepers. There is some 
evidence to show that the disease may be contracted by living in 
a leper community. 

In malaria the proof of the Plasmodium being the cause of 
the disease rests on the following facts : 

1. Its constant presence in the red blood corpuscles during 
the acute disease. 

2. Its definite development in association with the symptoms 
of the disease and with the recurrence of the attacks. 

3. Although not directly infective from man to man, it has 
been reproduced in a healthy man by mosquitoes, which have 
been artificially fed with the tertian parasite (p. 149). 

Sources of Infection. — In only a few instances, the infective 
agent has a separate existence for a greater or less length of 
time outside the body (p. 63) ; the main source of infection is 
the disease itself. 

Infection may occur during the life of the infected man or 
animal by the discharges (from the local lesion, from the 
mouth, lungs, intestine, or urine) passing from the body; or, 
after the death of the infected individual, by the contamination 
of the air. soil, water, or food with the infective agent. The 
source of infection must be looked for in pre-existing disease, 
aided, to some extent, by external conditions. On the whole, 
however, external conditions of light, heat, and moisture are 
hostile to the preservation of specific infective micro-organ- 
isms. In some instances they live a short time in water, but in 
other external media they are destroyed, probably by putrefac- 
tive bacteria. 



ii 4 INFECTION 

The following examples will illustrate these points : 

The pus cocci, as sources of infection, are derived chiefly 
from pre-existing abscesses, and are not found in garden soil, 
or water, to the extent which is sometimes stated. 

Staphylococci are found in the mouth, on the skin, in the 
vagina, and cervix uteri, and are present in the dust or air of 
badly ventilated rooms containing the sick. The streptococcus 
of pus and of erysipelas does not have any length of existence 
outside the body. It rapidly dies, even when most carefully cul- 
tivated. Some forms of streptococcus are found in the mouth 
and nasal passages. The pneumococcus and Friedlander's 
pneumo-bacillus are also found in the mouth. The infective 
cocci are, therefore, closely associated with man and animals, 
although they may not produce any lesion in a healthy indi- 
vidual. 

In the intestinal tract micro-organisms are normally found 
which are capable of infecting the body. The chief of these 
is the bacillus coli communis, which is passed out in the 
motions. This bacillus, obtained from the motions of a healthy 
individual, is pathogenic, and it is doubtful whether it is 
identical with the many forms obtained from water and soil 
which have been described as closely allied to it in artificial 
culture. 

In diphtheria the source of infection is the discharges from 
the diseased mucous membrane in cases of the disease; these 
may infect food products, especially milk, and so lead to the 
spread of the disease; otherwise, the diphtheria bacillus is not 
known to have a separate existence outside the body. This is 
also the case with tuberculosis, where the sources of infection 
are the sputum, the milk of cows suffering from tuberculosis 
of the udder, and the lesions of man and animals dead of the 
disease. 

In typhoid fever and in cholera the source of infection is a 
previously existing case of the disease, which may infect by its 
discharges, or the discharges may contaminate water, milk, and 
other foods. 

Modes of hi fee tion. — The infective agent must enter the 



MODES OF INFECTION 115 

tissues from without. The main channels by which it enters 
are as follows : 

1. By the mucous membrane of the mouth, of the pharynx, 
and of the gastro-intestinal tract. Sometimes it enters where 
there is no defect in the defensive mechanism; in other cases, 
where there is some slight abrasion of the mucous membrane or 
some previous lesion, such as ulceration, which has left a weak 
spot. From the nose, infection may pass to the frontal sinus 
or to the brain through the cribriform plate of the ethmoid 
bone. From the mouth or pharynx, infection may pass to 
the ear. to the salivary glands, or to the lymphatic glands 
below the jaw. From the duodenum infection may pass to 
the pancreas or gall bladder, and from the cecum to the ap- 
pendix. 

In this same group is the infection which occurs from the 
vagina to the uterus in the female, where there is some damage 
to the uterine mucous membrane, as after childbirth, or where 
the mucous membrane is intact, as in some cases of infection 
of the tubes and ovaries. Infection may also pass from 
the urethra or bladder to the vesiculse seminales and the tes- 
ticles. 

2. By means of the bronchial mucous membrane. The in- 
fection may occur in the mucous membrane itself, in the alveoli 
of the lungs, or may pass through the mucous membrane 
without apparent damage, and affect the bronchial glands or 
pleura. 

3. By inoculation. Infection by inoculation occurs in 
disease, frequently through an abrasion of the skin or mucous 
membrane of the mouth. It may also occur, however, by a 
puncture, either by a foreign body, or by an intermediate 
host, as in the case of filarial disease and malaria, and by 
the bite of an infected animal, as in the case of rabies, trans- 
mitted by the bite of the dog, wolf, or other infected ani- 
mal. » 

In individual cases it is not always possible to discover the 
site of entry of the infective agent into the body, and this is so 
because the site of entrance may be healed before the symptoms 
of the disease become pronounced; and, in the case of mucous 



n6 INFECTION 

membranes, infective agents may pass through into the tissues 
of the body without producing any local lesion, as is the case, 
for example, in some cases of septicemia, infective endocarditis, 
and tuberculosis. 

Course of Infection. — In infective processes there are two 
chief conditions to be considered : 

1. A generalized infection, in which the body is invaded by 
the living agent, which may become more or less generally dis- 
tributed in the tissues. 

2. A local infection and intoxication, in which the living 
agent forms a local lesion or focus, from which poisons enter 
the circulation and produce symptoms of the disease. 

An example of true infection would be anthrax, in which 
there is at first a local lesion, and subsequently a diffusion of 
micro-organisms throughout the tissues — the connective tissue 
as well as the organs. Anthrax is, indeed, one of the best 
examples of general infection by a micro-organism. In some 
cases of infection the distribution is not so general as in 
anthrax. Thus, in tuberculosis, the lesion may be for a long 
time only local, and then the disease becomes generalized. 
This takes place by the formation of foci in different parts in 
which the infective agent grows. A similar example occurs in 
some forms of pus infection. 

Examples of local infection and intoxication are found in 
tuberculosis, where symptoms are produced by the absorption 
of poisons from one local lesion ; in pus formation, where there 
is a single abscess, and in such diseases as diphtheria and tet- 
anus, which are the best examples of intoxication occurring 
from a local lesion. 

It is evident that, although infective processes may be divided 
into these two classes, yet the division is not sharply denned. 
In both cases there is a chemical poisoning of the body by the 
products of the infective agent. In one case, that of intoxica- 
tion, there is only a local growth of micro-organisms; in the 
other, that of infection, the growth is more generally dis- 
tributed. 

With regard to intoxication, it is not a matter of indifference 



COURSE OF INFECTION 117 

in the production of symptoms where the local lesion is. If 
the lesion is situated in the connective tissue or in a non-vital 
organ, the symptoms are those only of the poisons pro- 
duced by the infective agent. If, on the other hand, the 
local lesion leads to a greater or less destruction of a vital 
organ, such as the liver, kidney, suprarenal capsules, the 
thyroid, or the brain, special symptoms are produced, 
which may indeed mask the symptoms due to the infective 
process. 

After the infective agent has entered the body, two different 
events may happen. At the site of entry there may be a local 
lesion, and this may be followed by : (a) Intoxication of the 
body; or (b) Infection of the body. 

In many instances there is no local lesion produced, or, at any 
rate, so slight a one as to escape observation. This may occur 
in the skin, as in the inoculation diseases, or in the mucous mem- 
brane, in some cases of disease in which there is usually a local 
lesion. A local lesion varies, not only in extent, but in the 
result produced in the body. In some instances it is the only 
part of the body in which the bacteria grow, and it is by the 
manufacture of their poisons in the local lesion that an intox- 
ication of the body results. This occurs, for example, in 
most cases of diphtheria; in all cases of tetanus; in many 
cases of pus infection; in tuberculosis, and most cases of pneu- 
monia. 

In all these instances, whatever effect is produced in the body, 
the site of the local lesion, whether it be the mucous membrane, 
skin, lung, or other part, is the only place where bacteria grow, 
and where the toxins are manufactured. 

On the other hand, a local lesion may be followed by infection 
of the body, and the results of this infection are not, as a rule, 
the distribution of the bacteria in all the tissues of the body, 
but the production of a greater or less number of lesions in 
other parts of the body, due to the same cause as the local 
lesion. 

In anthrax, from the malignant pustule of the skin, or the 
lesion in a mucous membrane, bacilli enter the blood stream and 
the lymphatic stream, and are distributed to practically every 



n8 INFECTION 

tissue of the body, especially towards the end of life; in some 
places producing a local lesion, if the bacilli have grown there 
for any length of time. 

The diseases previously mentioned as usually showing a local 
lesion, followed by intoxication of the body, may also show 
infection of the tissues. Thus, in some severe and fatal cases of 
diphtheria, bacilli may be found, not only in the local lesion, but 
also in the lung, in the spleen, and even in the blood. 

The local lesion of pus infection, that is, the abscess, may 
lead to other similar local lesions in the tissues, the result of 
infection from the focus of suppuration. 

Similarly, tuberculosis, although it may remain localized for 
a long period, shows frequently a general infection of the body, 
characterized by the development of similar lesions in other 
parts of the body. 

Croupous pneumonia, which, in the majority of instances, 
forms only a local lesion, may in other cases show general in- 
fection, as when it is followed by meningitis, peritonitis, otitis 
media, and infective endocarditis. 

Typhoid fever is characterized by a definite local lesion, 
from which infection of the body occurs. Cholera, on the other 
hand, develops practically no local lesion in the intestinal tract, 
nor a general infection, but leads to profound and rapid in- 
toxication of the body. 

Mixed Infections; Concurrent Infections; Infections in 
Sequence. — The remarks last made apply solely to the specific 
effect of a single infective agent, but in cases of disease, in- 
stances commonly occur of infection by two or more infective 
agents, that is, a mixed or concurrent infection, or a different 
infection immediately following a first infection which pre- 
disposes to its development. There may be concurrent or 
mixed infections, as well as a secondary infection, from the site 
of the primary lesion, and different from the primary infection; 
or a secondary infection, not through the site of the primary 
lesion, but in some other part of the body, and due, primarily, 
to the effect of the first disease in lowering the resistance of the 
bodv- 



COURSE OF INFECTION n 9 

The subject now under consideration is by no means as yet 
fully worked out, but certain facts in connection with it are of 
importance. There are but few infective diseases which are 
antagonistic to each other; more frequently they aid one 
another. One of the commonest examples of mixed infections, 
or infections in sequence, is pus infection, which may graft 
itself on numerous diseases of the mucous membranes of the 
orifices of the body and upper respiratory tract. The subject 
is best illustrated by considering these infections mainly as 
regards the locality in which they arise. 

Primary Place of Infection, the Throat and Upper Air Pas- 
sages. — Diphtheria, in which the local lesion is in the throat or 
upper air passages, is frequently complicated by a pus infection 
of the glands below the jaw, and may also be complicated by 
empyema, the source of infection of which is also from the 
throat. Gangrene or putrefactive changes may occur in the 
throat. Similar results may be observed in scarlet fever. The 
broncho-pneumonia of laryngeal cases of diphtheria is due to 
the action of the bacillus itself, but croupous pneumonia may 
occur, due to the pneumococcus. 

Primary Place of Infection, the Intestines. — Examples of 
secondary infection not infrequently occur in typhoid fever. 
The ulceration of the intestine is due to the bacillus itself, but a 
streptococcus infection may occur subsequently, leading to sup- 
puration of the mesenteric glands and other parts ; or an infec- 
tion by the bacillus coli communis, without perforation of the 
wall of the gut. The mode of entry of these infections is 
through the mucous membrane of the intestine. Pneumonia, 
pleurisy, and meningitis are also observed in typhoid fever, and 
these may be due to the pneumococcus. 

The occurrence of tuberculous infection in association with 
enteric fever is a possibility, and it has been observed that a 
tuberculous process sometimes appears to begin after an attack 
of typhoid fever. It may be, however, that the acute disease 
only lights up a chronic tuberculous lesion. 

Primary Site of Infection, the Respiratory Tract. — Pneu- 
monia, due to the pneumococcus, may lead to bronchiectasis, 
and the bronchiectatic cavity may be subsequently infected by 



120 INFECTION 

pus cocci, or may serve as a cavity for the growth of putre- 
factive bacteria. Chronic tuberculous cavities may become in- 
fected by the streptococcus or the micrococcus tetragenus, and 
an infection of the lung by these micro-organisms may occur 
in such cases as a secondary effect. Infection by the influenza 
bacillus occurs in tuberculosis of the lungs ; in which also may 
occur infection by the pneumococcus and the streptococcus. 

The relation of the infections of scarlet fever and diphtheria 
is very important. The most common occurrence is an infec- 
tion in sequence; scarlet fever being followed by diphtheria. 
The order may, however, be reversed, and the two infections 
may progress concurrently. These two infections, indeed, 
appear to predispose to one another in a more marked way than 
in the case of any other infective disease. Scarlet fever may 
also be followed by other diseases, of which the most important 
are chicken-pox, measles, and whooping-cough. In other cases 
a definite attack of erysipelas follows it. On the other hand, 
scarlet fever infection does not appear to predispose to that of 
the typhoid bacillus. 

Influenza and varicella may run concurrently, or in sequence ; 
the latter being shown by its characteristic rash, and the former 
by its general symptoms. 

Whooping-cough and measles predispose to infection by pus 
cocci, the pneumococcus, and the bacillus tuberculosis. 

That certain toxic conditions of the body bear a relation to 
the supervention of infection is discussed elsewhere (p. 164). 
It may be stated here that chronic alcoholism leads more partic- 
ularly to infection by pus cocci, by the pneumococcus, and by 
the bacillus tuberculosis. Cirrhosis of the liver is also asso- 
ciated with these infections, which may run a rapid course. 
Chronic Bright's disease, in which there is evidence of a 
chronic intoxication, predisposes to the invasion of the body 
by the pneumococcus and by the bacillus tuberculosis : as also 
does diabetes. 

Examples of antagonism between infective diseases are not 
common. It appears, however, that pus cocci are, to some 
extent, antagonistic to the plague bacillus; and the bacillus 
pyocyaneus is antagonistic to the anthrax bacillus. 



INFECTION IN ANTHRAX 121 

Sequela: of Infection and Intoxication. — Recovery may take 
place from both these conditions — in some cases without leav- 
ing any trace of damage, in others with evidence of damage 
more or less permanent. One infective focus may lead to a 
permanent effect, although the process of infection ceases, as, 
for example, where an abscess damages a large portion of the 
liver, or where vegetations on the valves of the heart lead to 
their irregularity and contraction, and so to a permanent defect 
of the circulation. The after-effect of the process of intoxica- 
tion may be as important. Not only is there a general poison- 
ing of the cells of the organs, but there is a specific effect of the 
poisons on particular organs. The cloudy swelling of the liver 
and myocardium may lead to fatty degeneration. The in- 
toxication of the nerve cells may lead to their permanent 
damage, while the peripheral nerves may be specifically affected. 
In some instances, too, the kidney substance suffers more than 
that of the other organs. 

The Infective Process as it occurs in Disease in Man. 

1. Anthrax. — In the human being, anthrax is inoculated in 
the skin or mucous membrane of the mouth, and appears as 
a malignant pustule or carbuncle. Infection almost invariably 
comes from the undressed hides of animals (sheep, cattle, 
horses) dead of the disease. The pustule rapidly extends, pro- 
ducing a large brawny swelling. This contains the anthrax 
bacilli, chiefly between the cell elements, in the lymphatics and 
in the blood vessels. Intoxication and infection of the body 
follow. In the well-established disease, which ends fatally, 
bacilli are found in the neighboring lymphatic glands, in all 
the organs of the body, and, in some of these, may produce a 
local inflammatory lesion, if the patient has lived sufficiently 
long. The blood does not contain the bacilli until near death, 
or after death. No spores are at any time found in the bacilli 
in the body during life, but they may be found in the cadaver 
some hours after death. 

In animals, the disease takes three forms : either as a local 
lesion in the skin, as a gastro-intestinal, or as a respiratory 



122 INFECTION 

infection. In all cases a general infection of the body ensues, 
as in man. Both in man and animals the spleen is greatly 
enlarged : hence one of the names of the disease — splenic fever 
(milsbrand). 

Anthrax is, in animals and man, most commonly a pure 
infection. Experimental inoculation of the bacillus subcu- 
taneously in susceptible animals leads to inflammation at the 
site of injection, followed by an infection of the body, causing- 
rapid death; and, in such cases, after death, the bacilli are 
found in all parts of the body. 

2. Pus Infection. — The commonest agents in the production 
of pus are the pus cocci, the various forms of staphylococcus 
pyogenes and streptococcus pyogenes. But other forms of 
cocci may produce pus, such as the micrococcus tetragenus, the 
pneumococcus, the diplococcus intracellularis meningitidis, and 
the gonoeoccus. In certain conditions the bacillus coli com- 
munis and the typhoid bacillus produce pus, as well as the 
glanders bacillus, the tuberculosis bacillus, actinomyces, and 
putrefactive bacteria. 

The form of pus infection to be here considered is that 
produced by the staphylococcus and the streptococcus, and both 
of these may lead to two different forms of infection. ( i ) In 
one there is local suppuration, with or without formation 
of abscesses in different parts of the body : as, for example, 
in local abscesses and pustules; carbuncles, furuncles, and 
acute suppurative periostitis; in acute catarrhs, and in 
ulcerative endocarditis. (2) In the other form of infection 
there is septicemia, or a general infection and poisoning of 
the body; sometimes without any definite local lesion at the 
site of entrance of the coccus. 

The action of the streptococcus must be distinguished 
from that of the staphylococcus. It is, as a rule, more virulent, 
and tends more commonly to produce a general infection of 
the body than the staphylococcus. It thus leads to a spreading 
inflammation, or suppuration. It is the cause of spreading 
erysipelas, and it may be the cause in the throat of a 
fibrinous or croupous inflammation, with the production of 
a false membrane. It is, in all probability, the commonest 



PUS INFECTION 123 

cause of puerperal peritonitis and septicemia : a streptococcus 
enteritis is also recognized. 

2. Abscesses and Pyemia. — (a) Local Formation of Abscess. 
— The formation of an abscess may be purely local, and while 
producing intoxication of the body, may remain localized, no 
general infection occurring. 

(b) Spread of Pus Infection locally. — Another result which 
may happen is that, from the abscess, infection occurs along 
(a) the lymphatics to the nearest lymphatic glands, which 
then become infected, and may suppurate, and the disease 
may spread no farther than this; or (b) along the veins as 
far as a solid organ : as in pylephlebitis and in phlebitis of the 
superficial veins. 

(c) Spread by General Infection. — In other cases again, a 
general infection of the body occurs (septicemia, pyemia), 
and this results from the cocci being taken up by the 
lymphatics, and so carried into the blood stream, or throm- 
bosis of the veins occurring round the focus of suppuration; 
the thrombus disintegrating by the action of the cocci, and 
so being carried along the vessel to the heart. In both cases, 
the infective matter is carried to the right side of the heart, 
and distributed to the lungs, in which numerous foci of 
embolic suppuration may occur. This results in one form 
of pyemia, in which, besides the local lesion, or a secondary 
lesion directly connected with it, bacterial embolism occurs in 
the pulmonary circulation. This is observed from spreading 
abscesses in all parts of the body; in the pelvis, or from 
skin and gland abscesses. 

In other cases, embolic suppuration occurs in the course of 
the general systemic circulation, abscesses resulting in the 
brain, spleen, kidneys, joints, and sometimes the liver. It 
may be that in some cases, the minute cocci are carried 
through the blood vessels of the lungs, or by means of a 
patent foramen ovale (crossed embolism, Chapter XIII.), and 
so enter the left ventricle ; thence they are carried through the 
aorta to the organs of the body. This must be the explana- 
tion, for example, of the occurrence of abscess of the brain in 



I24 INFECTION 

some cases of empyema. But, besides this, there may be an 
infection of the valves of the heart, resulting in infective 
endocarditis, and, when this occurs in the mitral or aortic 
valves, the results are widespread septic embolism of the 
organs connected directly with the general systemic circu- 
lation. 

The local lesions produced in these conditions contain 
the infective agent: cocci are found in the pus, sometimes 
within the cells, but more commonly in the liquid. Strepto- 
cocci are not infrequently found degenerated. As a rule, 
however, they preserve their typical form. The parts of 
the body not affected by the suppurative lesions do not, as 
a rule, contain the cocci; these are, practically, absent from 
the blood. 

The sequelae of these forms of pus infection are practically 
nil. When recovery takes place, it is complete, especially 
in those cases in which the lesions have been in an indifferent 
tissue, such as the connective tissue. If, however, the lesions 
have been present in an important organ, such as the liver, 
heart, or brain, impairment of function may be subsequently 
observed. 

(d) Infective Endocarditis (Fig. 45). — One form of infect- 
ive endocarditis has been mentioned above as occurring as a 
secondary infection in pyemia. It also occurs when there is 
no evident primary local lesion, and may be produced, not 
only by the staphylococcus and streptococcus, but also by the 
pneumococcus, the gonococcus (very rarely), the bacillus coli 
communis, and some other forms of bacteria at present but 
little studied. Experimentally, infective endocarditis has been 
produced by injecting cocci after a lesion of the valves 
has been made. Besides the conditions already mentioned, 
infective endocarditis may be associated with pneumonia, 
influenza, dysentery, scarlet fever, chorea, and biliary infec- 
tion associated with gall-stones. The infection most fre- 
quently follows damage to the valves by rheumatism or scarlet 
fever. 

The results of infection of the valves of the heart depend, 
as indicated above, on the side of the heart affected (Fig. 101). 



PUS INFECTION 125 

Thus, if the valves of the right side be the seat of the 
lesion, the secondary lesions are found in the lungs — pul- 
monary infective embolism. If the valves of the left side 
be affected, the secondary lesions are found in the brain, the 
liver, spleen, kidneys, intestines, and other abdominal organs 
— systematic infective embolism. Medium-sized arteries may 




Fig. 45. — Infective endocarditis. 

The figure represents a vertical section of a vegetation of the 
mitral valve in a case of infective endocarditis. Below, a portion 
of the valve is seen (shown dark in the figure), which is invaded 
by leukocytes. Most of the figure shows above this the fibrinous 
cap of the valve, composing the vegetation. The fibrils of fibrin 
are seen, and the dark masses at the edge of the fibrin are masses 
of bacteria, which are seen invadingthe fibrin and disintegrating 
it, as well as growing in the substance of the fibrin. The par- 
ticular organism in this case was a staphylococcus. 

be blocked, and those of the limbs or intestines, leading to 
thrombosis, infective arteritis, or infective aneurysm. 

The localities in which the micro-organisms are found at 
death are the lesions in the valves of the heart and the 
secondary lesions. They are not found generally distributed 
in the blood or tissues. 

(e) Septicemia. — The term septicemia is applied to those 



i26 INFECTION 

cases in which a general infection of the body occurs, with or 
without any definite local lesion being produced. Examples 
which occur in man are not so well defined as those which 
can be produced by micro-organisms in animals. Thus, in the 
mouse, a typical septicemia is produced by the bacillus muri- 
septicus. The injection of this into an animal causes a general 
infection of the body, the bacilli being found at the site of 
injection, in all the organs, and in the blood at death. In 
the rabbit there are several micro-organisms which have 
the same effect ; the subcutaneous or intravenous injection of 
the pneumococcus, leads, for example, to a form of septi- 
cemia. A general distribution of the bacteria, without any 
special local lesion, may also follow the injection into the peri- 
toneum of virulent cultures of the bacillus coli communis and 
the typhoid bacillus. If similar virulent cultures be injected 
subcutaneously in the rabbit an abscess only results, without 
a general infection. 

Injection of the pyogenic cocci into the circulation of 
animals may lead to a septicemia, or, if they are mixed with 
some inert material, making them clog together, may produce 
abscesses in different organs. 

In man, septicemia is seen in cases of infected wounds, 
in puerperal septicemia and in infective endocarditis. In 
infected wounds there is an enormous growth of the bacteria 
(usually pyogenic cocci), and one result of this may be that 
previously stated, an intoxication of the body without infec- 
tion. A similar condition may occur in the puerperal state, not 
only in putrefactive decomposition of portions of retained 
placenta, but in cases of distinct infection of the placental site, 
which is practically an open wound. But infection of the body 
may occur from the infected wound, leading, as stated above, 
in some cases to a pyemia, with or without infective endo- 
carditis. In other cases, however, there is no definite local 
lesion produced in the body, but the micro-organisms are 
found in the internal organs, and in some cases in the 
blood. 

Again, cases of infective endocarditis which are primary 
may, in some instances, be followed by embolic abscesses — 






SEPTICEMIA, 127 

pyemia — but in other instances no definite local lesions are 
found, and the condition is practically comparable to the 
septicemia following an infected wound; in these cases the 
damaged valve, with its growth of micro-organisms, repre- 
senting the wound. Indeed, all these conditions show an 
infinite variety between typical embolic pyemia and typical 
septicemia. 

In some cases of septicemia no local lesion can be found, 
and the site of entry of the micro-organisms may be a small 
punctured wound, or some slightly damaged part of a mucous 
membrane. 

The lesions which are found in man in cases of septicemia 
are chiefly those which result from acute bacterial poisoning. 
Thus, the blood will be dark and fluid; there is post-mortem 
staining of the endocardium and of the vessels; there is fre- 
quently rapid decomposition of the body; the heart muscle, 
liver, and kidneys show cell degeneration, chiefly in the form 
of cloudy swelling, passing on to a fatty degeneration. The 
spleen is usually enlarged, soft, and diffluent, dark or choco- 
late red. Thrombosis of one of the peripheral veins may be 
found, with edema of the limb. There may be no local 
lesion present, or the wound through which the infection 
occurred may have healed, or it may obviously be an infected 
wound. 

Micro-organisms which produce these conditions may be ob- 
served microscopically, or obtained in culture from the different 
organs — the heart's blood, brain, kidneys, spleen, liver. They 
are found in the capillary blood vessels, between the cells, and 
sometimes in the cells. They are not usually found in the blood 
of the larger arteries or veins. A coccus of one or other form 
may be obtained, or, in other cases, the bacillus coli communis 
and the typhoid bacillus. 

3. Tuberculosis. — Tuberculosis may be local or generalized. 
The local lesion may be at the site of entry of the bacillus 
into the body, or, as in the case of bones, joints, and some 
other parts, the local lesion may be produced in a part 
remote from the site of entry, at which there is no discoverable 
lesion. 



12 8 INFECTION 

Generalized tuberculosis results from an acute infection 
of the disease, or as an acute dissemination from a chronic 
local lesion, but the bacillus is not generalized, as in cases 
of septicemia, generalization simply meaning the formation 
of more or less numerous local lesions in different parts of 
the body. The disease spreads after the bacillus has entered 
the body : 

1. By direct extension in the organ affected, either in the 
tissue of the organ or by open tubes — e. g., the bronchial tubes 
in the lung, and the intestine. 

2. Outside the part affected, by means of the lymphatics, to 
the nearest lymphatic glands. 

3. By means of the circulation; the vessel walls becoming 
affected, and the tuberculosis lesion discharging its contents 
into the blood stream. This is the mode of origin of remote 
tuberculosis, which must thus be considered as embolic in 
origin. 

The means of entrance of the bacillus into the body are 
mainly three : 

1. By inoculation. 

2. By inhalation. 

3. By the alimentary tract. 

Inoculation is accidental, as a rule, and occurs in the skin. 
It may also occur, however, in surgical operations on tuber- 
culous parts and may be followed by general infection of the 
body. The origin of disease by inhalation may be through 
the tonsils or the bronchial tubes, and the results may, in each 
case, be of two characters. There may be a local lesion of 
the tonsil — although this is not common — with a subsequent 
infection of the lymphatic glands below the jaw;, or there 
may be no obvious lesion of the tonsil, and the glands below 
the jaw and neck become tuberculous (scrofulous adenitis), 
or an affection of the middle ear through the Eustachian 
tube may result. Similarly, in the bronchial tubes the 
invasion of the tubercle bacillus may produce a local lesion 
in the bronchial mucous membrane, followed by an infection 
of the lung, and this is said to be a common result of 
infection in pulmonary tuberculosis (Birsch-Hirschfeld). But 



TUBERCULOSIS 129 

in some cases there is no obvious lesion of the bronchial 
mucous membrane or of the lung, and the bronchial glands 
become infected, as in the primary bronchial gland tuberculosis 
in children and in cattle; or the pleura, as in primary tuber- 
culous pleurisy. 

In the alimentary tract below the mouth, tuberculosis of 
the esophagus or stomach is extremely rare, even in the 
later stages of general tuberculosis. Below the stomach, 
however, both in the small and large intestine, primary 
tuberculosis is observed. Infection of the mucous membrane 
of the intestine occurs only when the bacillus is taken into 
the alimentary canal. Infection of the mucous membrane 
does not occur as a result of the generalized disease, 
although the mesenteric glands may in a few experimental 
cases become affected. As in the case of the mouth and 
the lung, there may be a local lesion, which is shown in 
the deposit of tubercle in the lymphoid tissue followed by 
ulceration, with a subsequent infection of the mesenteric 
glands; or there may be no local lesion at the site of entrance, 
but an infection of the mesenteric glands alone (tabes 
mesenterica). In the human subject, both with or with- 
out a local lesion of the mucous membrane, tubercu- 
lous peritonitis may occur. 

Whether or not a local lesion occurs at the site of entry 
of the tubercle bacillus into the body, appears to depend on 
the dose of the poison. With a large dose a local lesion 
appears invariably to be produced; with a small dose no 
local lesion is observed. There are, however, intermediate 
cases in which a very small local lesion is produced, for 
example, in the intestine, and the resulting generalized dis- 
ease is out of all proportion to the size of the lesion. These 
results have been proved experimentally by the feeding of 
animals with tuberculous material. 

A small dose of the poison tends also to limitation of 
the disease. If a large dose be inoculated into a rabbit or 
guinea-pie within three or four weeks there is dissemination 
of the disease to nearly every organ of the body, but, with 
very small doses, only a local tuberculosis may result at the 
9 



13° 



INFECTION 



site of inoculation, the disease 
practically not spreading even 
in ahundredand twenty days. 

Distribution of the Lesions 
in Man. — (a) Pulmonary 
Tuberculosis. — Tuberculosis 
may be primary or secondary, 
and the two commonest seats 
of primary tuberculosis are 
the lungs and the abdominal 
organs. 

The invasion of the 
disease in the lungs occurs 
in the manner already de- 
scribed, and the locality first 
affected is usually one or both 
apices (Fig. 46). A tubercu- 
lous lesion is here formed, 
which spreads by direct con- 
tinuity, as well as by means 
of the bronchial tubes and 
of the blood vessels. The 
inhalation of the infective 
material by the bronchial 
tubes leads to a tuberculous 
broncho-pneumonia, patches 
of which, more or less well 
defined in shape, are to be 
found in parts of the lung- 
remote from the primary 
lesion. Spread by the blood 
vessels occurs by the ulcera- 
tion of a tuberculous nodule 
into the lumen of the artery 
(Fig. 47) ; an infected em- 
bolus is then carried to 
another part of the lung, 



Secondary 




— Primary pulmonary 
tuberculosis. 

The diagram illustrates the lesions ob* 
served in primary lung tuberculosis. In the 
lungs themselves as seen at death, there is a 
cavity at the apex and more recent scattered 
lesions below, while the bronchial glands are 
affected from the lung. Other common sec- 
ondary lesions occur in the larynx and intes- 
tines by means of the sputum which is coughed 
up and swallowed. Tuberculous lesions in 
the other abdominal organs and in the brain 
are in this form of tuberculosis rare. 



TUBERCULOSIS 



I3 1 



where it gives rise to a tuberculous lesion, or most commonly 
a general miliary tuberculosis. The most usual appearance, at 
death, of the lungs in a case of chronic pulmonary tuberculosis 
is the presence, at the apex of one lung, of a cavity with 
thick walls, irregular sides, and traversed by the remains of 
bronchial tubes and vessels. Round the cavity the bronchial 




47-— Tuberculosis in an artery of the^lung, 



The figure shows a section of lung, some of the alveoli being seen, 
as well as a transverse section of a small branch of the pulmonary- 
artery. At one side the arterial wall is greatlv thickened, due to 
the formation of the tubercle, caseating in parts, and containing three 
or four gfiant cells. The figure shows that the tubercle in its devel- 
opment has separated the muscular coat from the internal coat. By 
therupture of this caseating mass into the blood stream arterial tu- 
berculous embolism occurs in the lung. If the wall of a vein is 
affected and the rupture occurs into the lumen, the infective material 
is carried to the left side of the heart, and so through the systemic 
circulation to the various organs of the body. 

tubes are dilated; below the cavity the tuberculous lesions 
are more recent, being less fibroid, and recent cavities may 
be observed. At the base of the lung the lesion is still more 
recent and this is also observed in the other lung. There 
may be no other tuberculous lesion in the body, and, in such 
a case as this, one lung becomes infected from the other, 
mainly by means of the expectoration from the primarily 



1 32 INFECTION 

diseased lung, which is inhaled into the healthy lung; or, in 
some cases, infection may occur by means of the bronchial 
glands, through which the lymphatics from both lungs pass. 

Primary tuberculosis of the pleura may also be a localized 
disease; it may, however, be associated with or followed by 
infection of the lung tissue and of the bronchial glands. 

Secondary Deposits in Pulmonary Tuberculosis. — Primary 
lung tuberculosis, when it becomes chronic, is not usually 
associated with generalization of the disease in the organs of 
the body, and Jhe parts commonly affected secondarily are 
those which are exposed to the action of the infective 
sputum from the lungs. This is the explanation of the 
occurrence of laryngeal tuberculosis and of tuberculous lesions 
in the pharynx and fauces, as well as of the more common 
intestinal infection. In a few cases isolated tubercles may 
be found in the liver and spleen; a few in the peritoneum 
or in the pelvic organs, and in these cases a secondary 
infection has taken place from the lungs by means of the 
general systemic circulation, the bacilli being carried by 
the pulmonary veins to the left side of the heart and so 
distributed. Such a mode of infection, however, is quite 
accidental. 

Pulmonary tuberculosis may itself be secondary, either to 
primary abdominal tuberculosis, to gland tuberculosis in the 
neck, or to cases of remote tuberculosis, such as those that 
occur in the joints, bones, generative organs, and kidneys. 
In such cases, however, the lesions produced are usually 
those characteristic of the acute, and not of the chronic, 
form. 

(b) Primary Bronchial Gland Tuberculosis (Fig. 48). — 
This is observed almost solely in children, and occurs in the 
manner already explained. It may result in a secondary tuber- 
culosis in the lungs, in the glands above the root of the lung; 
and by the lymphatics along the carotid artery the infection 
may be carried to the base of the brain, leading to tuberculous 
meningitis. In some cases an acute general tuberculosis' 
supervenes, by which not only the organs in the chest, but 
those in the abdomen, are affected. 



TUBERCULOSIS 



(c) Tuberculosis of the 
Glands of the Neck (Fig. 49). 
— This common form of the 
disease frequently remains 
localized. Its mode of origin 
has been already described. 
In some cases, however, 
spread of the disease occurs 
from the local lesion. This 
is usually downwards 
through the glands of the 
neck to the lungs, which be- 
come affected, and the associ- 
ation of tuberculous glands 
of the neck with tuberculosis 
of the lungs is by no means 
uncommon. Sometimes an 
acute or chronic tuberculo- 
sis follows. 

(d) Abdominal Tubercu- 
losis (Fig. 50). — This is 
not infrequently a primary 
disease, almost solely in chil- 
dren. It may exist in three 
different forms : 

1. With ulceration of the 
intestine, disease of mesen- 
teric glands, and tuberculous 
peritonis. 

2. With disease of mesen- 
teric glands with or without 
ulceration of intestine. 

3. With disease of mesen- 
teric glands and tuberculous 
peritonitis. 

Primary intestinal tuber- 
culosis, with peritonitis, may 
be followed by a general 




Fig. 48. 



-Primary bronchial gland 
tuberculosis. 



This diagram illustrates a not uncom- 
mon form of tuberculosis in children and in 
cattle. The primary seat of infection is the 
bronchial glands, the course being through 
the air passages. The lungs are secondarily 
affected from these glands,and it may be the 
lower cervical glands, while meningitis is 
common. General tuberculosis may result. 



*34 



INFECTION 



dissemination of the disease 
in the abdominal organs; the 
lymphatic glands, liver, and 
spleen, with sometimes the 
ovaries and kidneys, are the 
first affected. This is followed 
by acute tuberculosis of the 
lungs, and sometimes byP* 
tuberculous meningitis. All 
the lymphatic glands of the 
abdomen and thorax are not 
necessarily affected. In the 
abdomen the lumbar and~ 
celiac glands frequently 
escape, and, in the thorax, 
the anterior and posterior 
mediastinal, sometimes even 
the bronchial. When tuber- 
culous peritonitis exists, dis- 
semination of the disease to 
other parts is not so common, 
owing to the fact that the 
thickening of the peritoneum 
which ensues blocks the lym- 
phatics of the membrane it- 
self, especially that attached 
to the diaphragm, and so 
tends to check the convey- 
ance of the virus. 

(e) Remote Tuberculosis. — 
This includes cases in which 
so-called primary tuberculosis 
arises in the bones, joints, 
meninges of the brain, kid- 
neys, testicles, and ovaries. 
In many cases the site of 



Secomoa 




Fig. 49. — Primary cervical gland 
tuberculosis. 



In this case the glands below the jaw or 

entrance OI the baClllUS Can- in the upper cervical region are first afrect- 

. 1 . * - ed, and the lesion may remain stationary in 

not be dlSCOVered at the time this position, or a secondary lesion, as 

shown in the diagram, may occur in the 
lungs and bronchial glands. 



TUBERCULOSIS 



of death. In others, however, 
there is found an old tuber- 
culous focus, which may be 
very small in size, either at 
the apex of one or other 
lung, in the glands below the 
jaw, in the bronchial glands, 
or in the mesenteric glands. 

Tuberculosis in Animals. 
— The occurrence of natural 
tuberculosis in animals is 
mentioned elsewhere (p. 
1 60). The modes of infec- 
tion are not different from 
those already discussed with 
the human being. 

Experimental tuberculosis 
has thrown great light 
on the pathology of the 
disease, mainly on the occur- 
rence of the disease after in- 
oculation, feeding, or inhala- 
tion of material containing 
tubercle bacilli, and on the 
spread of the disease accord- 
ing to the virulence and dose 
of the tuberculous virus. 

Inoculation Experiments. 
In guinea-pigs (Fig. 51). 
after inoculation subcutane- 
ously in one or other groin 
with virulent tuberculous ma- 
terial, a local lesion is pro- 
duced in from seven to ten 
days; the inguinal glands 
become tuberculous in from 
seven to fourteen days, and in 
about the third week the dis- 




° s -Maxillar^ ' 




Secondary 



Secondary 



Fig. 50. — Primary abdominal 
tuberculosis. 

The channel of infection is here the intes- 
tine, and the local lesions resulting may be (i) 
intestinal ulceration and tuberculosis of the 
mesenteric glands, as shown in the diagram, or 
(2) no intestinal lesion, but tuberculosis of the 
mesenteric glands (tabes mesenter ca), or (3) 
with or without lesions described in (1) and (2), 
a tuberculous peritonitis. Secondary lesions 
occurs in the gastric glands, in the glands in 
the hilum of the liver, in the liverand spleen, 
and in the lungs. 



136 



INFECTION 



ease has spread to the internal lymphatic glands in the abdomen, 
and to the liver and spleen. In the fourth week the posterior 
mediastinal and bronchial glands are affected, and in about the 
fifth week the lungs. The disease may then spread into the 



Cervical Glands 



Axillary Glands 




Celiac Glands 



Lumbar Glands 



Fig. 51. — Tuberculosis in a guinea-pig, following inoculation. 

The lesions are colored red, and the course of infection is marked by arrows. The 
inoculation was in the right groin, and produced a local lesion which affected first the 
inguinal glands, next the right lumbar glands, and then the glands near the stomach 
and liver and the liver and spleen. Subsequently the posterior mediastinal and bron- 
chial glands were affected, and the lungs. In advanced cases both the axillary and 
cervical glands may be affected as well as the anterior mediastinal. The progress of 
the disease, therefore, following inoculation in the guinea-pig, is mainly by means of 
the lymphatic channels. 

glands of the neck and to the meninges of the brain. The 
mesenteric glands are affected only in very advanced tuber- 
culosis following inoculation; the suprarenal bodies and the 
kidneys are not affected. The fact of the mesenteric glands 
being affected after inoculation shows that the tuberculous 



TUBERCULOSIS 137 

infection inside the body can take place against the current of 
the lymph stream, a fact which is also shown in affection of 
the lungs following tuberculosis of the bronchial glands. 

Intraperitoneal inoculation of virulent tuberculous material 
produces an intense tuberculous peritonitis, with a great 
thickening of the omentum, and the deposit of miliary 
tubercles in both the parietal and visceral peritoneum. This 
occurs in about ten to fourteen days, at which period of the 
disease the lumbar, celiac, anterior and posterior mediastinal 
lymphatic glands may be tuberculous. The liver and the 
spleen, and even the lungs, may be affected at this time. In 
twenty-one days nearly every organ is diseased, except the 
gastro-intestinal tract, and, in the guinea-pig, the suprarenal 
capsule and kidney. 

Inoculation into the anterior chamber of the eye produces, 
in seven to ten days, a local tuberculosis, which spreads to the 
neighboring lymphatic glands, and finally to the lungs and 
other organs of the body. 

The facts shown by such experiments are the slow develop- 
ment of the disease, and the spread by means of the lymphatic 
channels. These results are the same, whether the inoculation 
material be obtained from the cow, or from the human being, 
as, for example, sputum, or whether a pure culture of the 
tubercle bacillus is used. 

If a small dose of the tuberculous virus is used for sub- 
cutaneous inoculation, the generalized disease is not produced, 
but an affection of the neighboring glands, to which the dis- 
ease tends to become limited. 

Feeding Experiments. — If guinea-pigs be fed with a single 
dose of virulent tuberculous material obtained from the cow 
or man, a local lesion is produced in the small intestine and 
cecum, which is visible to the naked eye in from eighteen 
to twenty-one days. From this lesion the disease spreads, 
in about twenty-eight days, to the mesenteric and cecal 
glands, and then to the celiac glands, the liver, spleen, posterior 
mediastinal, and bronchial glands and lungs, in this order. 

If pigs are fed with virulent tuberculous material, the 
course of infection is practically the same as. in the guinea- 



i 3 8 INFECTION 

pig, but, in this animal, the tonsil, as well as the intestine, is 
liable to be affected by a local lesion. There may, however, 
be only a small ulcer in the intestine, showing the site of 
entrance of the tubercle bacillus, and the internal glands 
and organs of the body may be extensively affected by the 
disease. 

If the material used for feeding pigs and calves is non- 
virulent, the result is somewhat different, and the main 
results may be stated as follows : ( i ) No local lesion is 
produced at the seat of invasion. (2) The lymphatic glands 
in connection with one or other part of the alimentary tract 
become affected by the disease; either the mesenteric, celiac, 
posterior mediastinal glands, or the glands below the jaw. 
(3) From this focus in the glands, the disease may become 
generalized; quite distant parts may be affected through 
the blood stream, namely, the lungs or the epididymis. 

Calcification of the tuberculous lesion is frequently observed 
in experimental tuberculosis in the larger animals, both in 
the lesions of the intestines, glands, and lungs, as it occurs 
in the natural disease in man and animals. The presence 
of calcification does not exclude the presence of living 
tubercle bacilli; some of the calcareo-caseous nodules are 
infective. 

Distribution of the Tubercle Bacillus in the Body. — The 
bacillus is present only in the lesions produced by the disease. 
It is seen in the earliest lesion, the miliary tubercle, in the 
caseous tubercle, chiefly in the periphery of the caseous matter, 
and, most abundantly of all, in the semi-liquid purulent con- 
tents of recent cavities; in these, as well as in old cavities, 
it is probable that the bacilli actually increase in numbers. 
Some die, some are expectorated, and all the bacilli found in 
the sputum are not living. 

In the calcareous masses bacilli are present, if any caseous 
matter still exists; but, in the completely calcareous nodule, 
no bacilli are discoverable. In some of the old calcareo- 
caseous masses the bacilli are very few in number, and stain 
badly, and are, no doubt, dying or dead. 

Tubercle bacilli are discharged from the body not only 



TUBERCULOSIS 139 

in the sputum, but in cases of tuberculous disease of the 
skin and upper air passages; in tuberculosis of the intestines 
and of the genito-urinary tract. The bacilli are not present 
in the healed lesions of tuberculosis, neither in a completely 
calcified nodule, nor in the lesions of the disease which have 
become completely fibroid. They are not found in the 
healthy organs, nor, except in rare instances, in the blood. 

Secondary Infection in Tuberculosis. — A tuberculous lesion, 
especially if ulcerated and communicating with the external 
air or with the alimentary tract, may become infected by 
other micro-organisms. Thus, from the alimentary tract 
putrefactive bacteria may develop in the lesion, and cause 
intoxication of the body. This may be observed, not only 
in intestinal tuberculosis, but also in the cases where a 
bronchial gland becomes adherent to the esophagus and 
discharges its contents into it. The more common invasion 
of the tuberculous lesion is by the pus cocci; either the 
staphylococcus, the streptococcus, or the micrococcus tetra- 
genus. This is likely to happen in tuberculosis of the nasal 
cavities, in tuberculous disease of the middle ear, and in 
pulmonary tuberculosis, more particularly where there is 
cavity formation. A pyemia or septicemia may result from 
this secondary pus infection in one of the manners previously 
described. A great role has been ascribed to the secondary 
infection of the streptococcus in pulmonary tuberculosis in 
the advanced stage in producing the symptoms and lesions 
observed. To this infection has been ascribed the high and 
continuous fever which is seen in such cases, as well as 
the non-tuberculous broncho-pneumonia observed in the lungs. 
Some of these effects may be due to the streptococcus infec- 
tion, but it is noteworthy that, not infrequently in such cases, 
the infection appears limited to the lungs. Too much stress 
has been laid on this secondary infection, but a streptococcus 
infection may occur and lead to empyema, or to abscesses in 
the brain. 

A pneumococcus infection may occur in tuberculosis, more 
especially tuberculosis of the lungs, and may result in the pro- 
duction either of pneumonia or of an empyema. Individuals 



140 



INFECTION 



the subject of tuberculosis are not resistant to the invasion 
of any infective disorder, and, in them, influenza runs a rapid 
course, the influenza bacillus being found with the tubercle 
bacillus in the expectoration. 

4. Syphilis. — Syphilis is an acquired disease, and results 
from inoculation of the virus, which produces a local lesion,, 
or hard chancre, followed by a general infection and intoxica- 
tion. Infection from the primary sore occurs first by way of 
the lymphatics, the nearest glands, such as the inguinal, being 
affected. Subsequent to this there is a general infection which 
results in lesions in the throat, in skin eruptions, and in loss 
of hair, as well as lesions in the bones. This is the so-called 
secondary stage of the disease. This secondary infection 
occurs by means of the blood stream. In a later stage the 
internal organs are affected. 

The lesions produced by the disease are, besides the primary 
sore and the secondary manifestations: (1) The occurrence 
of gummata, which are large, caseous masses developing in one 
or other part of the body; (2) the arterial disease which is 
described later (Chapter VIII.). These are the tertiary lesions 
which are produced by the infection of syphilis. 

Other lesions, however, are produced which result from the 
intoxication of the disease. These are albuminoid degenera- 
tion of the various organs (Chapter VII.) and certain forms 
of nerve degeneration, more particularly tabes dorsalis and 
general paralysis of the insane (Chapter XIX.). 

The gummata occur in the muscles, in the periosteum of 
bones, in the internal organs, such as the liver, spleen, kidney, 
lungs, and brain. The arterial disease is observed in and near 
gummata and other syphilitic lesions, but may be observed 
apart from these lesions, more particularly in the aorta and 
in the arteries of the brain. 

The process of infection in syphilis may be compared to 
that in tuberculosis. The first part of infection, as in tuber- 
culosis, is by means of the lymphatics. The subsequent 
course, however, of the infection differs from that of tuber- 
culosis in the fact that it is mainly through the vascular 
system. Unlike tuberculosis, syphilis may be transmitted to 






INTESTINAL INFECTIONS 141 

the offspring, producing what is called congenital syphilis. 
In some cases the lesions manifested in the infant are like 
the secondary manifestations in the acquired form, as regards 
the production of eruptions and of ulceration. Gummata are 
also observed. In addition, however, there are special lesions 
of the permanent teeth, more particularly of the incisors and 
canines, which become peg-shaped and notched, as well as of 
the cornea, which shows interstitial keratitis. Both acquired 
and congenital syphilis may lead to nerve degeneration. 

5. Intestinal Infections and Intoxications. — (a) Some of 
the intestinal infections are definite diseases, such as typhoid 
fever, cholera, dysentery, and ulcerative colitis, (b) In other 
cases there is a definite train of results referable to the 
intestinal tract produced by different micro-organisms, and 
mainly as a result of food poisoning. Three of these micro- 
organisms are Gaertner's bacillus, B. botulinus, and B. enteri- 
tidis sporogenes (Table, p. 59). Infection may also take place 
by the bacillus coli communis, the natural habitant of the in- 
testinal tract, (c) A third class of cases is where putrefaction 
occurs in the intestinal contents, and intoxication of the body 
ensues, and this kind of intoxication may occur simultaneously 
with one or other of the infections, (d) Acute infective 
enteritis may be due to one of the micro-organisms of food 
poisoning mentioned, or, in some cases, it may be due to a 
streptococcus, (e) Collateral infection may occur from the 
intestine, viz., of the appendix, of the bile-ducts or gall bladder, 
and of the pancreatic duct and pancreas. 

A. Typhoid Fever. — In typhoid fever the infection is by 
way of the intestines. The cases may be divided into two 
groups, in one of which, by far the more common, there is the 
characteristic ulceration of the Peyer's patches of the small 
intestine, and the solitary glands of the large intestine. In 
the second case there is no ulceration in the intestine, but there 
results the so-called typhoid septicemia. 

The typhoid bacillus has the peculiarity of being dis- 
tributed with difficulty in the tissues, even though it may 
cause death. Thus, in experiments with the typhoid bacillus, 
even if virulent, the subcutaneous injection of a culture leads 



i 4 2 INFECTION 

only to the formation of an abscess, from which the bacillus 
may be obtained in pure culture, the organism not being 
found in the blood or the internal organs of the body. The 
peritoneal injection of the virulent bacillus leads to the dis- 
tribution of the micro-organisms in the blood and organs of 
the body, but in some cases, especially if the bacillus is not 
very virulent, the distribution is irregular; it is usually found 
in the spleen, but may be absent from the blood and other 
organs. 

In cases of typhoid fever in man the organism can always 
be obtained from the mesenteric glands and the spleen; it is 
also present in the intestinal lesion. In the blood its presence 
is very irregular, and large quantities of blood have to be used 
for the diagnosis. It has been found in the blood of the 
heart, in venous blood, and in the blood of the skin eruption. 
In some cases it has been found in the kidneys, the liver, and 
in the bile. It is found, in a certain proportion of cases, in the 
urine, but in the stools it is not frequently discovered, except 
in cases where there is profuse diarrhea without putrefactive 
decomposition of the feces. The presence of the bacilli in 
these different parts does not necessarily lead to the forma- 
tion of any local lesion, but many of the " inflammatory ' ■ 
complications of typhoid fever are due to the bacillus. It can 
itself produce pus, as is seen from experiments in rabbits. 
In some cases of abscess formation in typhoid fever the 
bacillus is found in the pus, sometimes with the staphylo- 
coccus and the streptococcus pyogenes. The secondary lesions 
which may be produced are purulent cerebro-spinal meningitis, 
abscesses of the lungs and kidneys, cystitis, and acute inflam- 
mation sometimes leading to pus formation in the joints, bones, 
skin, testicle, lymph glands, parotid and thyroid glands. In 
the pus of these purulent complications, pus cocci alone may be 
found as well as the bacillus coli communis. 

Other cases of mixed infection occur in typhoid fever. The 
mesenteric glands may undergo gangrenous inflammation, 
and the bacillus coli communis is frequently present in these 
glands, as well as in the spleen, at death, and may be the cause 
of cystitis. 






INTESTINAL INFECTIONS 143 

In the very rare cases of typhoid septicemia, the micro- 
organism is found constantly in the spleen and lymph glands, 
and sometimes in the other parts already mentioned. Any 
gross lesion of the tissues may be absent. 

Cholera. — In cholera, the process of infection resembles, to 
some extent, that obtaining in typhoid fever. There is no 
gross local lesion in the intestinal tract, only the shedding of 
the epithelium, and many cases of cholera are good instances 
of the growth of a specific bacterium in the intestinal tract, 
and a subsequent intoxication of the body, resulting in death. 

The vibrio is frequently found in pure culture in the rice- 
water stools. It disappears within a fortnight. In most cases 
it is not found in the blood or internal organs. It has, how- 
ever, been found in the lungs, liver, kidneys, and spleen; very 
rarely in the blood. The explanation of this appears to be given 
by the results of experiment. With very virulent cultures of 
the vibrio, an intraperitoneal injection leads to the distribution 
of the micro-organism in the internal organs, as in the case of 
the typhoid bacillus. If the vibrio is, however, less virulent, 
its development tends to be limited to the peritoneal cavity, 
even though it may produce the death of the animal. 

The gross effects of the intoxication of the vibrio of cholera 
are shown chiefly on the side of the circulation; there being 
deep congestion of the liver and kidneys, with cloudy swelling 
and sometimes fatty degeneration of the cells of the tubules. 
Hemorrhagic spots may be present in different parts of the 
body. The right side of the heart is distended with dark blood. 

Dysentery. — The infective agency in dysentery has not yet 
been completely worked out, but there is some evidence to 
show that one form is due to an ameba, and another is due 
to a bacterium. 

Amebic Dysentery. — The amoeba dysenteries was described 
by Losch of St. Petersburg in 1875. It is found in the stools 
and in the liver abscess. It is spherical and of a greenish tint, 
and relatively large, being from 12 //to 26 u in diameter. Its 
protoplasm is divided into two parts, granular and dark inter- 
nally, homogeneous externally ("ectoplasm). It contains a 
nucleus, as well as red blood cells and bacteria, which it has 



i 44 INFECTION 

taken in from the intestinal contents. It moves by means of 
pseudopodia, and becomes immobile at 75° F. It is plentifully 
abundant in the stools at the acute stage of the disease, and is 
the cause of the liver abscess which sometimes follows, being 
found in the abscess walls, as well as in the pus. It frequently 
shpws degenerative changes. It has not been cultivated, but 
the disease has been transmitted to cats by means of rectal in- 
jections; when given by the mouth it produces no effect. 

The ameba, is not, however, the cause of all cases of dysen- 
tery, and endemic dysentery is possibly due to a bacterium 
which has been isolated by Shiga. This bacillus closely 
resembles, in its morphological characters, the bacilli coli 
communis and the typhoid bacillus. It forms an intracellular 
poison. A specific serum reaction is given by the blood of 
convalescents from this form of tropical dysentery. 

Ulcerative colitis is an infection of the large intestine, the 
cause of which is unknown. A similar anatomical change 
is observed in " Asylum " dysentery. 

B. Food Poisoning. — Cases of food poisoning are usually 
divided into two classes, in one of which the effects are ascribed 
to chemical substances present in the food when eaten — that 
is, the chemical products of bacteria which have developed in 
food and been killed by cooking. In the second class of cases, 
the bacterium, when taken in the food, is still living, so that 
an intestinal infection occurs. 

In both cases the food is spoken of as tainted food; but food 
which may cause poisoning, and even death, does not neces- 
sarily give any putrefactive odor. It may be doubted 
whether, in the absence of living bacteria, food can give rise 
to any serious poisonous effects. The amount of chemical 
poison swallowed in the absence of living bacteria must be 
very small. More and more evidence is forthcoming that food 
poisoning is due to the agency of specific pathogenic bacteria 
present in the food. The result is the growth of the bacterium, 
usually in the small intestine : an intoxication of the body fol- 
lows, or an infection of the organs of the body, sometimes 
with the production of remote lesions. 

Gaertner's bacillus has been shown to be the cause of some 






FOOD POISONING 145 

outbreaks of food poisoning. It is a bacillus closely allied to 
the typhoid bacillus, both in its mode of growth and in its 
poisonous chemical products (p. 93). It produces not only an 
intestinal intoxication, but also an infection of the body, and 
has been found in the liver and other organs of man in certain 
epidemics of food poisoning. 

The B. enteritidis sporogenes has been shown to be the 
cause of some cases of poisoning by milk. It is an anaerobic 
micro-organism, and produces its effect mainly by an intoxi- 
cation from the alimentary canal. 

To the B. coli communis must be ascribed some role in 
certain conditions of intestinal poisoning. It is a natural 
habitant of the large intestine, being found in the motions 
soon after birth and afterwards, and in the feces of all large 
animals. It is a pathogenic bacillus, closely allied to the 
typhoid bacillus and to Gaertner's bacillus. As obtained from 
normal fecal matter, it may not possess any great degree of 
virulence, but its virulence may be enormously increased arti- 
ficially, and is increased in certain intestinal infections. Thus, 
in typhoid fever, it has been shown to increase greatly 
in number and in virulence in some instances, and this may 
be the case also in other conditions in which there is no putre- 
factive decomposition of the intestinal contents. 

C. Putrefactive Processes in the Intestine. — Putrefaction of 
the intestinal contents, with a subsequent intoxication of the 
body, occurs in three different conditions : 

1. It accompanies certain intestinal infections — for e^amole, 
those of typhoid fever, dysentery, tropical diarrhea, and tuber- 
culous enteritis. 

2. It occurs in organic disease of the intestine, chiefly of 
the cecum, appendix, and large intestine. 

3. It may occur without the two previous conditions being 
present, and is then to be ascribed to a derangement of gastro- 
intestinal digestion permitting the overgrowth of putrefactive 
bacteria. 

The bacteria which produce putrefaction in the intestine 
are no doubt of many different forms, proteus vulgaris, P. 
Zenkeri, and bacillus saprogenes being the chief. The con- 



i 4 6 INFECTION 

ditions which favor putrefaction are: partaking of decom- 
posing food imperfectly cooked; stagnation of the intestinal 
contents, whether due to weakness of the muscular wall or to 
actual obstruction in the gut; and imperfection in the digestive 
processes in the stomach and small intestine, not only in the 
quality of the secretions, but in the deficient action of these 
on the proteids, and in a deficient absorption of the digestive 
products. 

The results of putrefaction in the intestine are not only 
an intoxication of the body by the chemical products (p. 71), 
but a local irritative effect on the intestine, causing congestion, 
an excessive secretion of mucus, sometimes slight hemorrhage, 
and usually the exudation of a quantity of liquid. Erosion or 
ulceration of the mucous membrane may follow, more particu- 
larly in cases where there is obstruction to the passage of the 
intestinal contents. 

D. Acute Infective Enteritis (Infantile Diarrhea, Cholera 
Nostras). — These conditions, although grouped together, are 
probably not due to one infection, and future research may 
show several different bacteria which may produce the results 
seen in infective enteritis. In such conditions the micro- 
organism is taken in with the food, or it is an infection start- 
ing with a bacterial growth in the mouth, and passing on to 
the intestinal tract. The association of this bacterial growth 
on the tongue, gums, cheeks, and fauces of children with acute 
infantile diarrhea is frequent. In infantile diarrhea putre- 
factive bacteria are found in the motions, especially the 
proteus vulgaris. In some cases the condition is found to be 
due to a streptococcus, so that a streptococcus enteritis must 
be recognized. The same may be said of the B. enteritidis 
sporogenes. 

The lesions found after death in such cases may be very 
slight, and not visible to the naked eye. Some congestion 
of the small intestine may be present, with some superficial 
loss of epithelium; gross lesions here, or in other parts of the 
body, may be absent. 

Some of these cases are examples of the growth of 
specific bacteria in the intestinal tract, with subsequent 



MALARIA 147 

intoxication of the body. In other cases erosion and ulcera- 
tion of the lymphoid patches in the large and small intestine 
have been found, with or without some enlargement of the 
spleen. These are cases of intestinal infection in which the 
bacteria invade the tissues of the body. 

6. Malaria. — Malaria is due to a protozoon, which was 
discovered by Laveran in 1880. It is found in the blood, 
inhabiting the red corpuscle, in which it undergoes its phases 
of transformation. It does not invade the tissues. Its action 
results in a disintegration of the red blood corpuscle, the 
coloring matter of which is set free as insoluble pigment 
(melanin). 

Three kinds of parasites are described according to the 
differences in their intracorpuscular phases of development, 
namely, the parasite of tertian, of quartan, and of. estivo- 
autumnal or irregular fever. Malarial fever has been pre- 
viously classified as quotidian, tertian, and quartan, according 
as to whether the attacks occur each day, every second day, 
or every third day, but it was found that there was no special 
parasite in quotidian fever, and that, in cases of a daily attack 
of the fever, this was due to the development of either of two 
groups of tertian parasites, or of three groups of the quartan 
parasite, maturing on successive days. 

The tertian parasite (Plasmodium vivax, Fig. 52) is the 
least virulent of the three forms. In its early stage, in the red 
corpuscle, it is seen as an oval body, which undergoes ameboid 
movement, and becomes pigmented. The phases of develop- 
ment of the parasite (schizogony) take forty-eight hours; 
segmentation takes place and the paroxysm occurs. The seg- 
ments form the rosette, and the rosette disintegrates, setting free 
the pigment and the young parasites (merozoites), which then 
undergo the same process of intracorpuscular development. 

The quartan parasite (Plasmodium malarias, Fig. 53) 
undergoes similar changes, but the chief difference is that the! 
period of development (schizogony) takes from sixty- four to 
seventy-two hours. The pigment granules are larger and 
blacker than those in the tertian form, and, during segmenta- 
tion, the pigment tends to form rays between the segments. 




148 INFECTION 

The segments ultimately set free are from six to ten or twelve, 
being fewer in number than in the case of the tertian parasite. 

The estivo-aiitumnal parasite (Levarahia malarise or Plas- 
modium immaculatum, Fig. 54) is more variable than the two 
already mentioned. It may form a hyaline body inside the 
red corpuscle, is more ring-like than the other two forms, and 

/ 

Fig. 52. — Malaria. Diagram of the intracorpuscular changes of the 
tertian parasite. 

(1) Shows the early stage of the merozoite within the red corpuscle; (2) to (2c) 
shows the various forms the parasite assumes during its growth and pigmentation 
(ameboid forms); (3) is the formation of the sphere (4) and (4a) the division of the 
parasite into segments or merozoites; while (5) shows the merozoites freed from 
the corpuscle; Phases (1) to (3) are those which occur in the prepyrexial stage of 
malaria, and take forty-eight hours to develop. 

1 2 2 a 2 h 

Fig. 53. — Malaria. Intracorpuscular changes of the quartan parasite. 

The main features in the phases of this parasite are the same in the tertian. The dif- 
ferences are that the pigment is blacker, that the segments, or merozoites, are fewer in 
number, and that the prepyrexial phases take seventy-two hours for their development. 

^ ir <£> w ^ i3§ %•& 

1 3 3* 3 h 3 C 2 




5 



Fig. 54. — Malaria. Intracorpuscular changes of the parasite of estivo- 
autumnal malaria. (See also Fig. 56.) 

The main features of the development are the same as in the tertian and quartan 

Farasite. The differences are that the parasite is much smaller and less pigmented, and 
requently assumes a ring-like form. Two parasites may be in one corpuscle as shown 
in (2). The merozoites are smaller and more numerous than in the case of the quartan 
parasite. 

has a shaded central part, with a smaller amount of pigment. 
Schizogony occurs in the spleen, bone-marrow, and liver, and 
at irregular intervals. 

Other forms of the malarial parasite are observed, and are 
mainly related to the sexual development of the parasite in 
the mosquito. These are the flagellate body, which is devel- 
oped from the intracorpuscular organism, and is freely movable 
when set free. The flagella are long compared to the body, 



MALARIA 149 

which contains granules of black pigment. They are most 
numerous in the irregular forms of malaria. The crescent 
form of Laveran is also frequently observed, and it may form 
a flagellate body. Ovoid forms are also seen (Fig. 56). 

The development of the parasite leads to the disintegra- 
tion of the red corpuscle, with the result, in prolonged cases, 
of producing anemia and pigmentation of the internal organs, 
the liver, spleen, and brain. The effects of the parasite, 
however, are not limited to this disintegration of the red 
corpuscle. It must also form a powerful poison, which 
causes the rise of temperature and other effects observed in 
malaria. More particularly in the quartan and irregular forms 
of malarial fever these effects are to be found; not only is' 
there high fever, but there is a profound nervous disturbance, 
as well as the production of hemorrhages. The blood is 
hydremic, and there may be a condition of hemoglobinemia, 
the liberated hemoglobin dissolving in the plasma. In chronic 
malaria there is melanemia, with deposit of pigment in the 
liver, spleen, and bone-marrow. 

The pernicious malarial fevers may show either profuse 
hemorrhage (mostly from the kidneys), or jaundice, or a pro- 
found effect on the gastro-intestinal tract or on the brain, with 
the production of delirium, ending in coma. 

Malaria has been conveyed from man to man by experi- 
mental inoculation, the period of incubation in the regular 
fevers being eleven or twelve days, in the irregular, from two 
to five days. 

The entrance of the parasite into the human being is not 
by means of the mucous membranes, but by means of the 
mosquito, one genus of which, anopheles, or the speckled-wing 
mosquito (Fig. 55), has been shown to be capable of harbor- 
ing the parasite after being fed with malarial blood, and the 
anopheles so infested has been shown, by direct experiment, 
to be capable of giving the disease to the human being. 
Anopheles is a genius widely distributed in the world, and is 
found both in malarious and non-malarious districts. In other 
genera of mosquito the parasite has been found not to live. 
The anopheles lives chiefly in swampy districts, containing 



i 5 o INFECTION 

almost stagnant pools. Its larvae will not develop in running 
water. 

It has been shown that healthy men can live in a badly 
malarious district, if, from sunset to sunrise, they live in 
mosquito-proof huts. The adult black races living in. malari- 
ous districts are more or less immune to the disease, some- 
times completely so. This immunity may be partly hereditary, 
but it has been shown that the children of these black races 
contain the parasite in their blood, so that the immunity of 




Fig. 55. — Anopheles claviger. 

This is one of the species of mosquito in which the 
malarial parasite undergoes a sexual generation (Fig. 56), 
and which conveys the infection to man by the introduc- 
tion, beneath the skin, of the parasite from the salivary 
gland. 

the adult may be due partly to heredity, but partly to an 
acquired faculty. 

The phases the material protozoon undergoes in the red 
corpuscle of man are only one part of its life history. 
Another phase of development takes place in the anopheles. 
The intracorpuscular development is called schizogony, and is 
asexual; the development in the mosquito is called sporogony, 
and is sexual (Fig. 56). The female mosquito when it sucks 
the blood of a malarial patient takes into its stomach the proto- 
zoon in all the phases of its intracorpuscular development. All 
die except the male and female gametocyte, which are pre- 
sumably derived from the merozoites. The male gametocyte 
becomes a flagellated body, and the flagella unite with the 



MALARIA 



151 



female gametocyte or macrogamete. The resulting conjuga- 
tion is a zygote, an oval-shaped body with pointed ends, and 
it is this zygote which undergoes further development in the 



<3 



Q? 



O 



* 



7 SCHIZOGONY (Asexual Generation)*. $ 
in Man. ^1 

® 

® 



6) o ts. a\ Merozoites 



Macrogamete^) © © ($)Microyamete 



I ' ^ Sporozoites. 

SPOROCONY (Sexual Generation) 

in the Mosquito 






Oocyst with Sporoblasts. 



Oocyst. 



w z w te or 

vermiculc. 



Fig. 56.— Malaria.— Diagram of the phases undergone by the parasite of 
estivo-autumnal fever in the red corpuscles of man and in the mosquito. 

The upper circle represents the process of Schizogony* or asexual generation occur- 
ring in man. The parasite develops in the red corpuscle, divides into segments or mero- 
zoites. which, set free in the blood, enter other red corpuscles, and so reproduce the 
disease without fresh infection by the mosquito. Sporogony, or sexual generation, which 
is shown in the lower circle, occurs only in the mosquito. There is a male and female 
element, microgamete and macrogamete* which are the cresents. The changes of shape 
these undergo are shown in the diagram, the femalebeing distinguished by the pigment 
surrounding the nucleus ; while in the male this is distributed throughout the proto- 
plasm. The male develops into the flagellated body: one of the flagella conjugates with 
the macrogamete, and the result is a zygote or vermicule, which becomes a spherical 
oocyst. This subsequently divides into numerous multiple cells, or sporoblasts. and 
these again into curved needle-shaped bodies, or sporozoites. These are the bodies 
which, when the mosquito stings, enter the blood and so into a red corpuscle. 

stomach of the mosquito, and finally projects from the stomach 
wall into the body cavity. Becoming spherical, the zygote 
divides, while still encapsuled, into sub-divisions called blasto- 
phores, and these blastophores subsequently develop into 
elongated bodies called sporozoites. The capsule inclosing 



152 INFECTION 

the sporozoite then ruptures, and the sporozoites are carried 
through the poison or veneno-salivary gland of the mosquito, 
from which they are inserted into the human being by the 
sting. Entering the red corpuscle, they undergo the phases 
which have already been described. These phases of develop- 
ment of the malarial protozoon do not stand alone in nature. 
Similar phases are shown by the coccidia, for example 
coccidium Schubergi, which is parasitic in the intestinal 
epithelium of a centipede, lithobius forficatus; and by other 
Protozoa more closely allied to the malarial parasite. The 
malarial parasite belongs to the order Hemosporidia of the 
Protozoa : other members of the order are like it ameboid, and 
show an alternation 'of hosts, schizogony occurring in a warm- 
blooded animal (mammal or bird), sporogony taking place in 
an invertebrate host. Many common birds are thus infected 
with hemoproteus (proteosoma) danilewskyi and halteridium 
danilewskyi; these live in the red corpuscle, but the inter- 
mediate host is not known. Piroplasma (apiosoma) bigem- 
inum is the cause of Texas fever in cattle. The disease, 
which is transmitted by the bite of ticks, is characterized by 
high pyrexia, loss of appetite, jaundice, emaciation, and 
frequently hemoglobinuria — hence the name " red- water " 
fever. A similar disease in dogs, called " malignant jaundice," 
is caused by piroplasma canis. 

Concurrent Infections with Malaria. — Dysentery, pneumonia, 
and typhoid fever are the chief infective diseases which may 
coexist with malaria, each due to its own infective agent. 
There is no necessity for the term typho-malarial fever, as in 
this case there is an infection by two distinct infective agents. 

Hemoglobinuric fever, which is also called black-water 
fever, bilious remittent fever, and West African fever, is a 
febrile disease, the most prominent feature of which, besides 
the rise of body temperature, is the occurrence of hemoglobin 
and its derivatives in the urine. The attacks are paroxysmal. 
At present its cause is not known, there being no direct 
evidence that the malarial parasite is responsible for its 
occurrence. 

7. Malignant New Growths. — Although the mode of origin 



MALIGNANT NEW GROWTHS 153 

of malignant new growths is not yet known, they may be 
conveniently considered in this chapter, in order to contrast 
and compare their characters with the processes of infection 
which have been discussed. 

Malignant new growths are of two kinds : cancer or 
carcinoma, which arises from epithelial tissues, either epiblas- 
tic or hypoblastic, and sarcoma, which arises from mesoblastic 
tissues. 

Cancer is at first a local disease arising either in epithelial 
tissue, or in one or other organ of the body. 

1. A primary tumor occurs and infiltrates the surround- 
ing parts, its spread not being limited by the periphery of 
the organ or part. In its growth it shows degeneration to a 
greater or less degree, frequently becoming adherent to the 
surface and ulcerating. 

2. It invades, by means of the lymphatic channels, the 
neighboring lymph glands, in which is reproduced a secondary 
growth resembling the primary. 

3. Subsequently secondary growths occur in other parts, and 
these are initiated by particles conveyed by the blood stream 
from the main growth. These secondary growths are called 
metastases. 

4. The growth is apt to be invaded at the surface by micro- 
organisms, producing putrefactive decomposition, and some- 
times an intoxication of the body. 

As illustrations of the spread of cancer in the body, the 
following examples may be taken. In cancer of the mamma 
the earliest part infiltrated is the axillary glands, followed by an 
affection of the glands above the clavicle. Infiltration occurs 
in the pleura and lung, while metastases may occur in the liver 
and spine. In epithelioma of the lip and tongue infiltration of 
the primary growth is seen, and invasion of the glands below 
the jaw. As a rule, metastasis does not occur. In cancer of 
the stomach, and of the colon and rectum, the neighboring 
lymphatic glands are affected, and metastasis occurs in the 
liver, the peritoneum being affected by direct invasion. 

The resemblance to infection, more particularly to that of 
tuberculosis and syphilis, which the mode of spread of cancer 



i 5 4 INFECTION 

shows, is evident from the following considerations: I. Cancer 
occurs near the surface and at places exposed to the influence 
of agents from outside, such as the mamma, tongue, lips,, 
esophagus, stomach, colon and rectum, vagina and uterus. 
In the gastro-intestinal tract it is noticeable that the most 
frequent seats of growth are the flexures or narrowings of 
the canal; as at the pylorus, in the cecum, at the hepatic and 
splenic flexures of the colon, at the sigmoid flexure, at the 
anus, and in the rectum near it. It might therefore, prima 
facie, be considered that cancer is due to some agent entering 
the body from without. . 

2. From the primary growth spread takes place by means 
of the lymphatics to the nearest lymphatic glands. Some 
instances may be quoted, although rare, where the glands 
are invaded without there being a primary lesion, as occurs 
in some cases of tuberculosis (p. 129). This occurs in chim- 
ney-sweeps' cancer, where the inguinal glands may be af- 
fected without a skin lesion. 

3. The occurrence of metastases, mainly through the circu- 
lation, is another point of resemblance to the mode of infection 
in tuberculosis and syphilis; but, whereas in these two in- 
stances the local lesion produced is the result of irritation 
of the tissue, in cancer the cells of the primary growth are 
actually carried by the lymphatic or blood stream, giving 
rise to the idea that the infective agent, if present, resides 
in the cells of the new growth. 

In the secondary growth there is a multiplication of the 
epithelial cells. This, when it occurs in a lymphatic gland, 
cannot be ascribed to the transformation of the cells of the 
lymphatic gland into epithelial cells, as this does not occur. 

4. After a primary growth has been removed — apparently 
completely — recurrence takes place. This might well be ex- 
plained by the fact that the removal, although complete to 
the naked eye, was not really complete. But not infrequently 
recurrence occurs in the scar of the operation, and at some 
distance from the periphery of the primary growth, as if 
indeed during the operation the cut tissue had become infected. 

5. Attempts have been made to discover the infective 



MALIGNANT NEW GROWTHS 155 

agent, but they have hitherto been unsuccessful. Microscopical 
examination of the cancerous tumor has shown the presence 
of ovoid " nucleated " bodies in the epithelial cells, which by 
some are considered parasitic and by others as degenerated 
nuclei. Attempts to cultivate an infective agent have not 
hitherto been successful. Cultures have been obtained 
from some specimens of cancer of certain blastomycetes 
or yeast-like organisms, but although these have proved 
pathogenic to certain animals, their injection has not yet 
succeeded in producing a carcinomatous tumor. It may 
be that the animals used were not susceptible to the infec- 
tion, and so the characteristic new growth was not produced. 
Attempts to inoculate fresh cancerous tumors into various 
animals, both domesticated and in monkeys, have uniformly 
resulted in failure, whether the inoculations were made by 
grafting, by the injection of an emulsion of the growth subcu- 
taneously, intravenously, or intraperitoneally; or whether the 
growth was used for inoculation after being kept for a long 
period in different kinds of earth, so as to enable the possible 
infective agent to develop extra-corporeally. It may be that 
the only animal susceptible to human carcinoma is man. 
Growths with a similar structure also occur in domesticated 
animals, and inoculation of the tumor from one animal into 
another of the same species has been successful. 

Sarcoma is, as has been said, of mesoblastic origin. It 
arises primarily more particularly in the lymphatic glands 
and in the bones and periosteum, but it may also arise in 
the organs of the body. Its mode of spread is from gland 
to gland, or by infiltration. Metastasis occurs by the blood 
stream and not by the lymphatics, the lungs being commonly 
affected, as well as other organs. 

The Effects of Malignant New Growths. — Malignant new 
growths — whether carcinoma or sarcoma — unless removed, 
invariably lead to death. After removal there may be no 
recurrence for some years. Subsequently, however, recurrence 
usually takes place, not necessarily at the seat of the primary 
growth, but elsewhere in the body. Malignant growths cause 
death in different ways. They are associated with wasting and 



156 INFECTION 

anemia, which are parts of the cancerous " cachexia." Death 
may be caused : 

1. By infiltration and destruction of important organs and 
tissues, such as the liver, kidney, lungs, heart, blood, and brain. 

2. By interference with the passage of the food, or with 
its digestion and absorption. Interference with the passage 
of the food occurs, for example, in cancer of the esophagus, 
pylorus, and colon; with the digestion of the food in ob- 
struction at the pylorus, which is followed by bacterial decom- 
position of the stomach contents ; or by cancer of the pancreas, 
which destroys the organ supplying one of the main di- 
gestive juices. 

3. Part of the fatal result is sometimes due to the invasion 
of the tumor by micro-organisms, which may invade the tissue, 
causing gangrene, as in rupture of carcinoma of a hollow 
viscus. Putrefactive decomposition of the intestinal con- 
tents may also occur. 

It may be said that the evidences of an intoxication in 
cancer are but slight, inasmuch as the profoundest effects 
on the body are observed in cases where an important organ, 
such as the liver, is destroyed, or where the cancer occurs in 
the alimentary tract. Pyrexia does not occur in carcinoma, 
but is observed in some cases of generalized sarcoma. 

Malignant disease, more particularly of the abdomen, is 
associated with fatty degeneration of the heart, liver, and 
kidnevs. which perhaps may be due to a cancerous intoxica- 
tion, but is also to be ascribed to the malnutrition of the pa- 
tient, owing to the deficient amount of food assimilated. 



CHAPTER VI 

infection — continued 

IV. Immunity 

Two facts are of importance in commencing the study of 
immunity : 

1. Specific bacteria are not infective to every class of animal. 

2. Recovery takes place in infective disease. 

. That specific bacteria are not infective to every class of 
animal shows that there is a condition of the body which pre- 
vents their growth and the formation of their toxins. That, 
in a large number of cases of infective disease, recovery takes 
place, shows that after a time the body becomes resistant to the 
further growth of the bacterium. Moreover, in cases of the 
same infection in different individuals, there is a varying degree 
of severity of infection, that is a varying degree in the growth 
of the bacteria. An animal or man may therefore show 
susceptibility to an infective disease, or refractoriness ; and 
both these qualities may be possessed, to a varying extent, not 
only by different animals, but also by different individuals of 
the human race. 

Immunity may be defined as a conditon of the body, natural 
or acquired, rendering it resistant to the invasion of one or more 
infective disorders. 

In natural immunity the disease is not acquired under the 
ordinary conditions of existence, but in some cases the specific 
germ, when inoculated, may produce a disease, which develops 
in a modified or an acute form. In other cases, even the in- 
oculation of the specific virus is without result, so that, besides 

157 



i5» 



INFECTION 



natural immunity, there is a special immunity and an inocula- 
tion immunity of animals and man to disease. It is evident 
that inoculation is a much more severe test of immunity than 
the observations of natural immunity. 

Natural Immunity. — There are certain infective diseases 
which are observed naturally in man only; others in animals 
only; and a third group of diseases which are present in both 
man and animals. 

Infective Diseases occurring in Man only. 



Typhoid Fever. 

Cholera. 

Diphtheria 



Malta Fever. 

Leprosy. 

Gonorrhea. 



Amebic Dysentery. 
Malaria. 



Sleeping Sickness. 



Scarlet Fever. 

Measles. 

Whooping-Cough. 

Variola. 

Syphilis. 

Mumps. 



Typhus. 
Dengue. 
Yellow Fever. 
Beri-Beri. 
Delhi Boil. 
Frambesia. 



Diseases occurring in Animals only. 



Swine Plague (Pigs). 
Contagious Pleuro-pneumonia 

(Cattle). 
Distemper (Dogs). 
Diseases allied to Malaria. 



Horse Sickness (Horses). 
Black Leg (Sheep). 
Nagana, Tsetse Fly Disease 
(Herbivora chiefly). 



Infective Diseases occurring in Man and Animals. 



Tuberculosis. 

Anthrax. 

Glanders and Farcy. 

Pyemia. 



Tetanus. 

Foot and Mouth Disease. 

Plague. 

Actinomycosis. 



Such a classification of disease as regards its distribution in 
the animal kingdom, is provisional, inasmuch as the infective 



NATURAL IMMUNITY 159 

agent is not known in all the diseases named, and further 
investigation may limit the number of diseases to which man 
alone and domestic animals alone are subject. Although 
disease may be observed in man alone, yet the bacterium may 
produce disease and. death in some of the lower animals when 
injected into the body. 

Taking the first group of diseases observed in man only, 
typhoid fever and cholera have not been observed in any animal 
in the form in which the disease occurs in man, although the 
infective agent in each case is fatal to certain animals when 
injected either subcutaneously or intraperitoneally, and in both 
diseases, under certain conditions, infection may take place by 
means of the alimentary tract, the usual mode by which the 
disease is conveyed in man. 

Diphtheria may possibly, in future, be shown to be a natural 
disease in certain animals — for example, cats (Klein) and 
horses (Cobbett) ; but, for the most part, it may be considered 
as a disease peculiar to man, although the bacillus is highly 
infective to rodents, cats, horses, and cows. The Malta fever 
coccus is infective to monkeys, but rodents, guinea-pigs, and 
mice are non-susceptible, unless the bacillus is injected into the 
brain beneath the dura mater (Durham). Leprosy, as far as 
is known, is a disease peculiar to man. and cannot be inoculated 
into animals. Relapsing fever is observed chiefly in man, but 
can be inoculated into monkeys. 

With regard to the other diseases mentioned in group 3 of 
the first class, the infective agent is unknown, or, at any rate, 
extremely doubtful. No animals are known to suffer from 
scarlet fever, measles, syphilis, or from the other diseases men- 
tioned. The infective agent is, moreover, unknown, and in- 
jection of the morbid secretions has not produced any diseased 
condition in the lower animals. 

The second class of diseases, namely, those peculiar to 
animals, includes some, like pleuro-pneumonia, distemper, and 
horse-sickness, in which the infective agent is unknown; but 
such diseases do not occur in the human being, nor does swine 
plague or black leg. 

The tsetse flv disease, which affects herbivora and carnivora 



160 INFECTION 

in certain parts of Africa, is not transmissible to man; the 
infective agent (trypanosoma Brucei) does not flourish in the 
human body. 

The class of diseases occurring in both man and animals is 
gradually extending, and investigation has brought to light 
many curious facts in the natural immunity of animals to cer- 
tain diseases, as distinguished from inoculation immunity. 

Tuberculosis is a natural disease in man, cattle, and pigs; 
it is a rare disease in goats, sheep, horses, and dogs. Both 
goats and dogs are capable of being infected by the tuberculous 
virus, but, in the case of the latter animal, large doses have to 
be given. It is unknown as a natural disease in wild animals ; 
yet most of them can be infected by it. Metchnikoff has- 
recorded an extraordinary resistance of an Algerian rat 
(meriones) to the disease after inoculation. Guinea-pigs and 
rodents are very susceptible to the disease on inoculation, 
although they do not suffer naturally from it. 

In the case of anthrax, man, cattle, sheep, pigs, goats, and 
horses develop the disease naturally. Algerian sheep are re- 
fractory; adult white rats, dogs, and pigeons are very refrac- 
tory to the disease on inoculation. 

Diphtheria may be inoculated with success into rabbits, 
guinea-pigs, dogs, cats, monkeys, and cows, the inoculation 
resulting in a fatal infection. White rats and mice are very- 
refractory to inoculation, and mice are also not susceptible to 
the toxin of diphtheria. 

To inoculation by the pneumococcus, rabbits and mice are 
susceptible; guinea-pigs and fowls are refractory, especially 
fowls. 

However interesting these facts are, their discussion does not 
lead to any clear idea on the subject of immunity. From' 
the facts which have been given, it is clear that natural 
immunity is purely a relative term : that whereas, for 
example, the disease may be peculiar to man or an animal 
in the sense that it does not occur naturally, yet neither man 
nor animals may have an inoculation immunity against the 
disease. 

Examples of extreme refractoriness of animals to disease- 



NATURAL IMMUNITY 161 

occurring in man are of great importance, especially in those 
cases, such as typhoid fever and cholera, where the infective 
agent is known. Until, however, the infective agent in all 
these diseases has been separated and studied, but little progress 
can be made in the determination of the causes of natural 
immunity. In some instances, so-called natural immunity 
appears to depend mainly on absence of infection. In others, 
however, there is a natural defense in the body against the 
invasion of the infective agent. 

The Natural Defense of the Body against the Invasion of 
Micro-organisms. — Bacteria are not present in any of the 
tissues of the healthy body. They exist in the mouth and 
throat in greater or smaller number. They are taken in with 
the food, but do not develop in the stomach. They begin to 
develop in the small intestine, especially towards the lower 
end, and are present in large numbers in the contents of the 
large intestine. In the upper part of the nasal cavity they are 
not present, and in the normal bronchial tube they are, as a 
rule, absent. They are present in the vagina, but not in the 
urethra. Where bacteria exist normally in the body, they 
may be considered as practically outside the tissues. Most 
of the bacteria found in the localities mentioned are non- 
infective, but some are capable of producing disease; as with 
the pneumococcus. which may be present in the mouth ; 
micrococcus tetragenus, which is also present in the mouth 
secretion, and bacillus coli communis, which is found, with 
other bacteria (chiefly putrefactive) in the intestine. There 
is some evidence, also, that pathogenic bacteria may be present 
in the mouth and intestine without giving rise to disease, as in 
the cases in which the diphtheria bacillus is found in the throat, 
and no lesion is present. 

The natural defenses of the body against the invasion of 
bacteria are three in number : 

i. An unabraded and healthy mucous membrane. 

2. The hydrochloric acid of the gastric juice, which is 
secreted on the entrance of food into the stomach, at a time 
when the bacteria are also present. 



162 INFECTION 

3. The natural antagonistic action of certain substances 
present in the liquids and cells of the body. This action is 
sometimes referred to as the " bactericidal action " of serum, 
or as due to the presence of defensive proteids or alexins. 
These terms, however, are too narrow to express this antago- 
nistic action, which will be more fully discussed when the ques- 
tion of artificially produced immunity is considered. 

With regard to the defense of the mucous membrane 
against the invasion of micro-organisms; this exists partly 
in the epithelium (whether stratified, columnar, or ciliated), 
but is, no doubt, partly due to the active phagocytosis which 
occurs in the mucous membrane, especially in the tonsils 
and those parts of the intestine which contain lymphoid 
tissue. 

The hydrochloric acid of the gastric juice inhibits the 
growth of bacteria, or actually kills them. Normal gastric 
juice will, for a long time, remain undecomposed. In the 
ordinary healthy person, bacteria taken with the food do 
not develop in the stomach. Most of them, however, are 
simply inhibited in their growth, which takes place in the 
small and large intestine. To some pathogenic bacteria the 
gastric juice is destructive, for example, those of cholera and 
tubercle; but this is not the case with the typhoid bacillus, 
as it can grow in a liquid containing a small quantity of 
hydrochloric acid. A diminished inhibition of the bacteria 
in the stomach occurs in cases where there is a diminution 
in the secretion of hydrochloric acid, so that, in such cases, 
pathogenic and other bacteria can pass through the stomach 
unharmed. 

The factors in immunity and in infection are three in 
number : 

1. The degree of virulence of the infective agent. 

2. The dose of poison. 

3. The degree of resistance of the body to the invasion. 
The virulence of the infective agent has already been dis- 
cussed (p. 65). . 

Within certain limits, the dose of the poison is important. 
A smaller amount of weak virus may not infect, while a large 



NATURAL IMMUNITY 163 

amount will, and the amount of virus which will cause infection 
depends, to some extent, on the mode in which it is introduced 
into the body. Infection directly through the circulation re- 
quires the smallest dose, and is as a rule the most certain. In- 
fection beneath the skin, and into the periotoneal cavity, also 
requires a small dose to be effective; but infection through in- 
gestion, that is, by the way of the alimentary tract, is the most 
uncertain of all, owing to the exposure of the bacteria to the 
resistant mucous membrane, to the action of the gastric juice, 
and to the action of the bacteria (acid-forming and putre- 
factive) of the intestinal contents. 

The degree of resistance of the body is difficult, if not 
impossible, to define in natural immunity; but, in artificial 
immunity, there is evidence to show that this resistance is, 
in the main, due to antagonistic substances in the tissues of 
the body. 

The natural resistance of the body may be increased by the 
production of artificial immunity, and it may be diminished by 
various means. The factors that are usually considered under 
the heading Etiology of Disease are those which, to some 
extent, are concerned with the resistance to infective disease. 
Such factors are the influence of age. sex, climate, surround- 
ings, food, and heredity. But these factors are, in the main, 
indefinite, and their detailed discussion would not serve any 
useful purpose in a work on Pathology. 

Hereditary predisposition to infective disease may be depend- 
ent not only on the special character of the surroundings, but 
also on the vigor of the individual, and on the nature of the 
infection. The absence of vigor of the individual may depend 
on deficient development or nutrition of certain parts, or on the 
weakness of some of the natural defenses against the invasion 
of infective disease. Tuberculosis, for example, is but rarelv 
directly inherited, although, doubtless, hereditary predisposition 
to the infection exists in certain cases. Syphilis is the best 
example of hereditary disease, and, in this case, there may be 
germinal infection. In the case both of tubercle and of anthrax, 
infection may be passed to the offspring by means of a placental 
infection. 



164 INFECTION 

The influence of a previous condition of the body, as predis- 
posing to infection, cannot be disregarded. These conditions 
may be divided into two classes, both of which may be consid- 
ered under the heading of the Influence of Injury. 

The Influence of a Previous Injury as Affecting Infection,. — 
i. The injury may be mechanical, as in the blow on the chest 
which precedes the development of pulmonary tuberculosis in 
some cases. A chronic lesion of the skin may also lead to infec- 
tion, and the blow which sometimes precedes cancer of the 
breast may also be placed in the same class. 

2. But the most important previous injury which predisposes 
to infection is one in which the body has been exposed to the 
action of the poisons of a previous infective disease, or to the 
continued action of a poison, such as alcohol. Thus infection 
by tuberculosis follows whooping-cough and measles ; or pneu- 
monia may follow these. Pus infection follows that of 
diphtheria, scarlet fever, and other conditions. Syphilis and 
alcoholism predispose to tuberculosis; alcoholism also to the 
invasion of the pneumococcus and of pus cocci. In chronic 
Bright's disease, the infection of tuberculosis or of the pneumo- 
coccus is frequently observed. 

Many attempts have been made experimentally to diminish 
the resistance of the body to an infective disease. Thus, as 
regards the anthrax bacillus, to which pigeons are naturally 
resistant, invasion of the body was aided by previous starvation 
of the animals. White rats, however, were not affected in this 
way, but might be rendered susceptible to the bacillus by giving 
them hard work to do on an unsuitable diet. In frogs, the 
anthrax bacillus does not develop, but if the animal is kept at 
a temperature of 25 to 35 C, development of the bacilli is 
observed. In these experiments the chief agents used were 
the alteration of the surroundings of the animal or of its 
food. 

Attempts have been made to prove experimentally that both 
the spleen and the pancreas are necessary for the continuance 
of either natural or acquired immunity. Thus it is stated that 
the removal of the spleen removed the artificially produced 
immunity of rabbits to tetanus, and that the removal of the 



AR TIFICIAL IMMUNITY , 65 

pancreas destroyed the natural immunity of pigeons to anthrax. 
These statements, however, are not correct, and more particu- 
larly with regard to the spleen. It has been shown that the 
presence of this organ is not necessary for the continuance of 
immunity. 

The resistance of the body, however, may be diminished by 
means of chemical substances which are injected into the body 
at the same time as the bacillus. Part of this subject has 
already been considered, as it is one of the means by which the 
virulence of bacteria is increased (p. 67). But other facts in 
this connection are that sugar injected with the staphylococcus 
pyogenes aureus increases the suppuration caused by this micro- 
organism and chloroform narcosis removes the natural immu- 
nity of frogs and rats to the anthrax bacillus. 

On what resistance to disease actually depends, these experi- 
ments, however, shed no light. More help has been gained by 
the study of the means and results of producing artificial 
immunity in animals; that is, increasing the resistance of the 
body to infective disease. 

Artificial immunity may be produced in three different 
ways : 

1. By the injection of an attenuated living virus. 

2. By the injection of the chemical products of the virus. 

3. By injecting the blood serum of animals made immune 
by one or other of the first two methods. 

The first two methods are practically the same, inasmuch 
as the bacterium acts by means of its chemical products, but 
the action of the living virus cannot be controlled so well as 
that of the chemical poison. The production of immunity by 
the injection of the living virus is frequently referred to as 
actkr immunity or preventive inoculation, and this may be 
extended to include the method when the chemical poison alone 
is used. Passive immunity is produced by the third method 
mentioned. 

Illustrations of the Production of Artificial Immunity 

(A) By the Attenuated Virus. — 1. Vaccinia (Jenner). — The 
process of vaccination confers immunity against subsequent 



66 



INFECTION 



vaccination, and a relative immunity to smallpox. After the 
insertion of the lymph into the skin, a dry papule appears, which 
becomes a vesicle, and subsequently a pustule ; a scab then forms 
and falls (Figs. 57 and 58). 




Fig. 57. — Smallpox and vaccinia. 

Figs. 57 and 58 show the appearances resulting from vaccinationfand 
smallpox inoculation in the arm. 

In Fig. 57 the appearances on the fourth and fifth days are shown, 
that resulting from smallpox on the left and from vaccinia on the right. 
The differences are the greater size of the smallpox vesicle and^the 
more intense areola round it (G. Kirtland). 

The duration of the different stages is as follows : 

First to fourth day .... Dry papule. 

Fifth to tenth day .... Vesicle (umbilicated). 

Eleventh day . . . . . Pustule. 

Fourteenth to twentieth dav . . Scab forms andrfalls. 



The general symptoms which are associated with this infect- 
ive disease are a rise of temperature, slight in extent, which 



IMMUNITY IN VACCINIA 



167 



begins at about the third day and may last until the eighth day. 
There may be malaise, headache, and the other symptoms 
associated with a slight infection; rashes may appear on the 
body, erythema, roseola, urticaria. Vaccinia may be purely 




■rr. 




Fig. 58. — Smallpox and vaccinia. 

This figure shows the same arm as in Fig. 57, but on the tenth and 
eleventh days. The differences in the appearance are still more marked. 
The site of inoculation of smallpox shows a large crop of vesicles sur- 
rounded by a dark areola, and also vesicles lying outside the areola. 

The vaccinia arms, on the other hand, show on the same day a well- 
marked vesicle and areola, with a tendency to drying up of the vesicle 
on the eleventh day (G. Kirtland). 

localized to the seat of inoculation, but it sometimes gives rise 
to a general eruption, which is preceded by the formation of 
supernumerary vesicles round the point of inoculation. Some- 
times the vaccinated individual inoculates other parts of the skin 
by scratching the seat of inoculation, and so conveying the 
poison. In the blood of the vaccinated some leukocytosis is 
observed at about the third day, but it disappears early in the 
second week. 



1 68 INFECTION 

The result of the inoculation with the smallpox virus in the 
human being is very similar to that of vaccination, but both 
the local process and the general symptoms are more intense. 
Secondary vesicles are very numerous, and the secondary erup- 
tion more common. Inoculation may result in an attack of 
smallpox, proving fatal. 

Immunity Produced. — The receptivity to successive vacci- 
nation diminishes during the second week, at about the 
ninth day, and is extinct before the fourth week; that is, at 
this period immunity to vaccination is established, and sub- 
sequent vaccination produces no result, within a certain variable 
number of years. As in all other cases the immunity gradually 
diminishes, and is finally lost, so that re-vaccination can now 
be successful. 

Whether the immunity so produced is an immunity to 
smallpox is a question which has been much discussed. It 
is probable that several different kinds of lymph have been 
used since the introduction of vaccination, and it is possible 
that some of these lymphs did not contain the true infective 
agent. The original idea was that cowpox was smallpox 
modified by being passed through the cow. Recent additions 
to our knowledge on the subject may be summarized as 
follows : Monkeys are susceptible to both smallpox inocu- 
lation and vaccination, and inoculation runs a course as in man. 
Inoculation of variola and vaccinia gives rise to a specific in- 
flammation, and from these areas are obtained different 
kinds of lymph, such as variolous lymph and vaccine lymph. 
When the calf is used it is called calf lymph, and that from the 
human subject is referred to as humanized lymph. It has 
been found that, in many cases, inoculation with vaccine 
lymph protects against the subsequent inoculation of vario- 
lous lymph, and vice versa. This is an important fact, as 
showing that variola and vaccinia are closely allied diseases, 
and that they are probably due to the same infective agent. 
Immunity is specific, and such immunity as has been described 
could not be produced if the two diseases were essentially 
different. 

There is a large amount of evidence to show that, in man, 



IMMUNITY IN ANTHRAX j6 9 

vaccination protects against smallpox, the protection in some 
instances being absolute, in others relative; that is, although 
the vaccinated individual may develop smallpox, it runs its 
course in a modified form, and the mortality is much less than 
in unvaccinated individuals. 

The micro-organisms which have been found in vaccine 
lymph, and not variolous lymph, are mainly staphylococci, such 
as occur in the skin. Another organism has also been found, 
which is a small bacillus, best stained by carbol-methylene blue. 
It is very slow in growing, and has been cultivated in the hen's 
egg. "Whether it is the true infective agent or not is as yet 
unproved. 

2. Vaccination was the precursor of the modern methods 
of preventive inoculation. In the modern instances, however, 
the infective agent is known, and so the process has been more 
fruitfully studied than that in vaccination. In this method 
the infective agent has to be attenuated to prepare the animal 
for the strong dose of poison which is subsequently in- 
jected. The subject of attenuation has been already discussed 
jp-65). 

Anthrax. — Pasteur attenuated the anthrax bacillus, by 
•growing it at a temperature of 42 C. in broth. He thus 
obtained his premier vaccin, which was injected into a sheep, 
as a preparation for a dose of the stronger poison. In this 
method of attenuation the bacilli, in less than a month, lose 
their virulence, so that they are no longer fatal to rodents, 
and they do not produce spores. The deuxieme vaccin was 
made by the same method, but the bacilli were allowed to 
grow only twelve days, so that they were much more virulent 
than those of the premier vaccin. 

Sheep were first treated subcutaneously with five drops of the 
premier vaccin, and, twelve days later, with the deuxieme vac- 
cin. Fourteen days later it was found that immunity had been 
established, inasmuch as a virulent culture of the bacillus pro- 
duced no symptoms. Injection of this virulent culture increases 
the immunity already produced. The immunity lasts in sheep 
about nine or ten months. It has not been found verv effective 



1 7 o INFECTION. 

against intestinal anthrax infection, but it has undoubtedly led,. 
in France, to a great reduction in mortality from anthrax. 
Immunity may also be produced by the chemical products of 
anthrax (p. 174). 

Fowl-cholera, etc. — Pasteur also showed that immunity could 
be produced against fowl-cholera by the same method as with 
anthrax. 

Other instances of producing immunity by means of the 
living virus are chiefly of historical interest, as, in the main, 
the chemical products of the bacteria are now used, and not 
the living bacterium. The tetanus bacillus and the diph- 
theria bacillus which have become attenuated by age have 
been said not to act as a vaccin, but the tetanus bacillus 
when treated with trichlorid of iodin, an antiseptic which 
diminishes its activity, was found to produce a moderate 
degree of immunity. So, also, the injection, at first, of very- 
small doses of the tetanus bacillus into dogs, which are refrac- 
tory to its action, produced immunity, which was increased by 
continued treatment with the bacillus, in gradually increasing 
doses (Tizzoni). 

The diphtheria bacillus was attenuated by growing it with 
trichlorid of iodin, and was found to produce immunity; 
also by heating a week-old culture to 6o° to 70 C. In the 
latter case it was found that immunity was not produced 
until about fourteen days after the injection of the 
vaccin. 

Cholera (HafTkine). — In this case cultures of two degrees of 
virulence are used : the weaker first, followed by the virus 
exalte. Ordinary cultures of the vibrio are not fatal to animals 
by subcutaneous injection. Large doses, however, of young 
cultures, injected into the peritoneal cavity of a guinea-pig, are 
fatal in twenty- four hours. 

To obtain the virus exalte, the peritoneal fluid is removed 
from such an animal, and incubated at 37°C..in broth. This 
is then injected into the peritoneum of another guinea-pig, 
and so on, until an exalted virus is obtained, capable of killing 
a guinea-pig in very small doses (p. 65). Before injection, the- 
exalted virus is grown on agar, and an emulsion is made of 



IMMUNITY IN CHOLERA AND PLAGUE i 7 i 

one culture, in broth, the organisms being sometimes killed by 
the addition of 0.5 per cent, of carbolic acid. The weak virus 
is obtained by growing the vibrio with a current of air passing 
over it. It is found that, in guinea-pigs treated first with the 
weak virus, and then with the exalted, the animals are protected 
against many times the fatal dose of the virulent living vibrio, 
injected intraperitoneally. 

In man, the symptoms produced by the subcutaneous inoc- 
ulation of the virus are those of general malaise, with some 
swelling at the site of inoculation and some fever. From 
statistics obtained from India, in which preventive inocula- 
tion against cholera has been extensively used in epidemics, 
it would appear that it is in some degree successful, not 
so much in preventing the incidence of the disease, as in dimin- 
ishing the mortality. The immunity produced is relative, and 
not absolute. 

(B) Immunity Produced by the Chemical Products of the 
Infective Agent. — 1. Plague (Haffkine). — The plague prophy- 
lactic is obtained by growing the bacillus in a liquid medium 
for five or six weeks, at the end of which time the bacilli 
are greatly degenerated. The bacilli are then killed by heat- 
ing the liquid to 65 to jo° C. for one hour. It loses its toxic 
properties, but it was found to confer immunity in rabbits 
(which are naturally resistant to plague), whereby they could 
resist the injection of ten or fifteen times the lethal dose of 
virulent plague bacilli. 

The dose given in man is 3 c. c. This causes fever, with 
headache, nausea, and malaise, and some swelling and pain 
at the site of inoculation. Comparing the results as regards 
the mortality in the inoculated and uninoculated, it appears 
that this is less in those who have been inoculated, although 
the incidence of the disease was not appreciably diminished. 
What immunity is produced lasts only a short time, possibly 
six months. 

2. Typhoid Fever ("Wright). — The method of antityphoid 
vaccination is practically the same as that of cholera and plague. 
The bacillus is grown in broth for three to four weeks, the 
culture being then sterilized, so that the liquid injected contains 



1 72 INFECTION 

chiefly the bodies of the bacillus, with the intracellular poison, 
previously described (p. 95). 

The dose given is 1-2 to 1 1-2 c. c. for the first vaccination. 
The strength of this is 2-5 of the lethal dose for a guinea-pig' 
weighing 250 grams. In the second vaccination, which must 
not be done within ten days or a fortnight after the first, once and 
a half to twice the original dose maybe injected subcutaneously. 
The symptoms produced in man by the poison come on in 
one to six hours, usually about the third hour, and are shown 
first by malaise and some tendency to faintness. Fever 
ensues, the temperature rising to 101 to 103 F., and usually 
persists for eighteen or twenty- four hours (Fig. 40). The 
degree of bodily depression is sometimes considerable, but 
no serious results have supervened. At the site of inocula- 
tion there are tenderness, redness, and swelling. The swelling 
may be considerable, but it passes off, as a rule, in forty-eight 
hours. 

Experiments on animals have shown' that this vaccin 
increases the resisting power against the living bacilli, and 
the blood of the inoculated patients gives the typhoid serum 
reaction. At first, however, there is an increased susceptibility 
to infection, and it is only later that there is a marked increase 
in the bactericidal action of the serum. Small doses of the 
vaccin act better than large doses. 

Although the results of preventive inoculation cannot be, 
as yet, accurately gauged, it would appear that, in some 
instances, it has diminished the mortality from typhoid fever, 
although it has not appreciably diminished the incidence of 
the disease. 

3. Hydrophobia (Pasteur). — The infective agent of hydro- 
phobia has not yet been isolated, but the toxin which has been 
found has many characteristics in common with those produced 
by some bacteria. The infective agent has been described 
variously; as one of the blastomycetes, as a bacillus, and as 
a protozoon, but none of these has been proved to be the real 
cause of infection. 

T,he virus itself is very sensitive to external conditions; it 
is destroyed by one hour's exposure to 50 C, and is killed by 



IMMUNITY IN RABIES 17 3 

putrefaction. Drying* also diminishes its virulence. Pasteur 
obtained a constant strength of the virus by passing the 
virus of the dog through a series of rabbits or guinea-pigs, 
and he produced immunity in dogs by subcutaneous injection 
of a weak virus, followed by that of a stronger. The most 
effective way of introducing the virus into the body is beneath 
the dura mater. 

Pasteur attenuated the virus by drying the spinal cord of 
rabbits dead of the disease in a sterile jar of air containing 
potash solution. The virus diminishes in strength up to the 
fourteenth day, when it dies. The weak virus, in different 
stages of the drying, is used in the early stages of producing 
immunity against the strong poison. More than this, it was 
found that, after infection had actually occurred, and before 
symptoms had developed, treatment of the dog or of man by 
graduated doses of the virus produced an immunity against 
the disease. 

The treatment in man extends about twelve days, and is 
begun by using 2 c. c. of emulsion of dried cord twelve to 
fourteen days old. Every day, or every second day, emulsion 
of cords containing a stronger amount of poison is given, until, 
at the end of the treatment, emulsion of cord only one day old 
may be given without harmful effect. In severe bites treatment 
is somewhat more rapid than this. The results obtained show a 
remarkable diminution in the mortality following bites by 
rabid animals. 

The principle underlying the process is that, after infection 
has occurred, provided the period of incubation is sufficiently 
long, the symptoms of disease and a fatal result may be obviated 
by producing a rapid immunity, and this principle has been 
extended to the treatment of other infective diseases, notably 
diphtheria and tetanus. 

An anti rabies serum has been prepared from the blood of 
animals which have been immunized by the injection of the 
hydrophobia virus attenuated by digesting it with pepsin. This 
serum has the power, not only of producing immunity in ani- 
mals, but of preventing the development of symptoms after 
the virus has been injected (Tizzoni). 



i74 INFECTION 

It has previously been said that the process of immunization 
-which takes place when an animal is treated with the living 
infective agent is practically the same as the production of 
immunity by means of the chemical products of the infective 
agent, but, in the latter case, the dose of the poison can be more 
accurately regulated. In most instances the object is to obtain 
the most virulent toxin possible, the dose of which can be deter- 
mined after dilution. 

4. Anthrax. — Toussaint and Chauveau showed, some years 
ago, that a culture of the bacillus of anthrax, killed by heat, 
was a vaccin against the bacillus. Hankin separated an albu- 
inose from cultures of the bacillus, and found that it afforded 
partial protection against the subsequent injection of the 
bacillus, and that for this purpose only very small doses of the 
albumose were required. 

These results are interesting from a historical point of view, 
as following Woolridge's researches on chemical vaccination 
against anthrax. His work must be considered as the earliest 
which indicated the more recent discoveries in the production 
of immunity by chemical products. He found that the injection 
of the substance which he called tissue fibrinogen, which is 
really a nucleo-albumin (Chapter XIII.), partially protected 
rabbits against the infection of the bacillus of anthrax, and that 
a better effect was produced if the bacillus were grown in 
solution for a short time before it was injected. Only a partial 
protection was obtained. 

5. Bacillus Pyocyaneus. — This bacillus is pathogenic for 
rabbits and guinea-pigs, and produces both edema and abscess. 
Subcutaneously injected, it produces an abscess, and, if the 
animal recovers, immunity is produced. 

Sterilized cultures of the bacillus are also found to produce 
immunity, as well as the filtered urine of rabbits which have 
been inoculated with a virulent culture of the bacillus. The 
serum of animals immunized against the bacillus, if inoculated 
with the bacillus, causes the micro-organisms to agglomerate 
and sink to the bottom of the tube {Agglutination, p. 186), 
whereas, grown in ordinary serum, they become diffused 
through the liquid. 



IMMUNITY IN DIPHTHERIA 175 

These results with the bacillus pyocyaneus show, not only 
that the chemical products do produce immunity, but that- 
the serum and urine contain substances in which the immuniz- 
ing properties exist, and that these substances may be formed 
during the occurrence of the infection. Moreover, these sub- 
stances have a special effect on the bacillus itself, causing it 
to agglutinate. 

In connection with this part of the subject, Metchnikoff 
showed that the blood of rabbits killed by the bacillus of 
hog cholera acted as a vaccin when heated between 54 and 
58° C. 

6. Diphtheria. — In diphtheria there is the best example of 
the production of immunity by means of the chemical products 
of the bacillus. A toxin of a high degree of virulence 
is obtained by growing the bacillus in broth distinctly alka- 
line, and sometimes with a current of air passing over the 
surface. The virulence of the toxin has already been consid- 
ered (p. 79). 

When gradually increasing doses of this toxin are injected 
into a refractory animal, such as the horse, each dose produces 
a local reaction, with some degree of fever and illness, all of 
which diminish as the treatment is continued. At the end 
of a varying time the serum of the blood removed from the 
animal is found to possess highly immunizing properties. In- 
jected into an animal, it will prevent any results following 
the subsequent injection of a fatal dose either of the bacillus 
or of the toxin; injected with the toxin in certain propor- 
tions of each, it completely prevents the development of any 
symptoms; injected, in certain conditions, after the toxin 
or the bacillus has been injected, it will also prevent any 
symptoms or fatal results occurring (Fig. 59). The substances 
in the blood, therefore, are not only antimicrobic, but are 
antitoxic. They, moreover, antagonize the toxin, and can 
counteract the action of the toxin even if subsequently injected; 
this allows of their being used for the treatment of the disease. 
The exact nature of the reaction between the toxin and anti- 
toxin is discussed on p. 179. 

The antitoxic properties of the serum of the treated horse 



176 



INFECTION 



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NATURAL IMMUNITY 177 

last many months, and can be kept up by repeated injections 
of the toxin. Instead of using the toxin in the initial 
stages, the so-called serum toxin may be used, which is 
obtained by growing the bacillus in a mixture of broth 
and serum (p. 79), whereby not only the toxin, but also 
the albumoses, are used for injection. By preparing the horse 
with this serum toxin, more rapid immunization is said to be 
produced (Cartwright Wood). 

7. Tetanus. — By a method similar to that used in diphtheria, 
a tetanus antitoxin has been prepared from the horse, which 
has the same properties as the diphtheria antitoxin. It is 
antimicrobic and antitoxic, and can be used for the treatment 
of the disease. The treatment, however, has not yet been 
so successful as in the case of diphtheria, owing, possibly, to the 
firm combination which takes place between the tetanus toxin 
and the nerve cells (p. 185). 

8. Ricin and Abrin, and Snake-Venom. — It is important 
to compare these results with the experiments which have 
been performed with the allied vegetable poisons, abrin and 
ricin. and with snake-venom. With abrin and ricin immunity 
has been produced by the repeated injection of very small doses, 
or, better, by gradually increasing doses or by feeding the ani- 
mals with the poison. In the animals that are made immune 
in this way. the poisons do not cause conjunctivitis when 
applied to the eye, nor do they produce any symptoms or lesions 
when subcutaneously injected, so that the immunity is com- 
plete. A very high degree of immunity may be obtained. It 
develops slowly, and in the first few days of experiment is not 
very obvious. The blood-serum of the immunized animals con- 
tains a substance which is antagonistic to the action of the 
poisons. There is both an antiabrin and an antiricin, each 
specific for its own poison, but not for the other. 

These results show that, even with a non-bacterial poison, 
the tissues of the body are capable of reacting against it, pro- 
ducing substances which antagonize its action. 

The same has been found with regard to snake-venom (Cal- 
mette, Fraser). Repeated and minute doses of cobra-venom 
injected into the horse produce, in time, an immunity against 



178 INFECTION 

the fatal dose of the poison, which, for the horse, is 15 mgm. 
of dried cobra-venom. Five mgm. of this poison is fatal to a 
dog, and about 31 mgm. to a man, mice and rats being still 
more susceptible to the poison. 

It was found that 5 c. c. of the serum of the immunized 
horse protected against a fatal dose of the venom in a rabbit, 
and that this serum was also curative, being capable of saving 
several animals after a fatal dose of the poison had been in- 
jected. This curative effect has been proved to occur in actual 
snake-bites in man, the dose given being from 25 c. c. to 30 c. c. 
The venom, therefore, not only produces in the body a substance 
antagonistic to itself, but this substance can produce immunity 
after the poison has been injected. The antivenene of cobra- 
venom will not protect against the daboia venom. It is possible, 
however, that a partial protection is obtained with the cobra 
antivenene in the case of the poison of most venomous snakes. 
It is now the practice to prepare the serum by injecting horses 
with a mixture of cobra and viperine venom. 



The Blood and Tissues in Immunity. 

The researches of recent years into the changes which occur, 
more especially in the blood, in immunity, have revealed the fact 
that the injection of certain substances (poisons, ferments, and 
some proteids) into the body, leads to the formation of sub- 
stances which are antagonistic to the action of the poison or 
substance injected. These antagonists are grouped under the 
heading of anti-bodies. They are sometimes referred to as 
anti-sera, inasmuch as they are chiefly found in the serum of the 
drawn blood. The formation of these substances takes place 
not only when bacterial poisons and others allied to them are 
injected, but even when a ferment, such as rennin, is injected, 
or when proteids foreign to the body or animal cells are used 
for injection. 

These anti-bodies may be grouped as follows : 

Anti-Bodies. — 1. Antitoxins and anti ferments ; 2. Agglu- 



ANTITOXINS AXD ANTIFERMENTS 179 

tinins; 3. Coagulins and precipitins; 4. Cytotoxins (hemoly- 
sins, bacteriolysins, spermatoxin, etc.). 

1. Antitoxins and Antifcrments. — Antifcrmcnts are pro- 
duced when certain ferments are injected into the animal body. 
These anti ferments prevent the action of the original ferments. 
The best known of these is antirennin, which is produced in 
goats by the repeated injection of rennin. The serum added to 
a certain quantity of milk prevents its coagulation by means of 
rennet. An anti-emulsin has also been prepared, an anti- 
trypsin, and an antifibrin-ferment. The antitoxins are sub- 
stances which completely counteract the effect of the toxins. 
Examples of these may be instanced in the diphtheria and 
tetanus antitoxins, in the antitoxin of the bacillus pyocyaneus, 
and in antivenene, antiabrin. and antiricin. 

The most extensive researches have been done with the 
diphtheria and tetanus antitoxins, and with antivenene, and the 
following remarks apply chiefly to these. 

(a) Relation of Antitoxin and Toxin. — If a toxin and anti- 
toxin be mixed together outside the body before being injected, 
it is found that no symptoms are produced on injection, if they 
are present in certain proportions, and this is true in whatever 
part of the body the injection is made — under the skin, into 
the peritoneal cavity, or into a vein. 

For the purpose of estimating the strength of both, the 
diphtheria toxin and antitoxin artificial units have been 
established (Ehrlich). The toxic unit, or simple lethal dose, 
is the amount of toxic broth which is fatal in four days to 
a guinea-pig weighing 250 grams. The antitoxin immunity 
unit is the amount of serum which will completely neu- 
tralize the effect of 100 simple lethal doses of toxin for 
a guinea-pig of the weight mentioned; that is, this amount 
of serum mixed with toxic broth containing 100 lethal 
doses, injected into the guinea-pig, causes no symptoms. 
For reasons presently to be stated, Ehrlich found it was 
preferable to have a standard antitoxic serum, and, in 
the actual testing, to determine the strength of each sample 
of manufactured toxic broth against this standard anti- 
toxin. 



r8o INFECTION 

There is a difference between the physiological action of 
toxic broth which is just made and that which has been kept 
for some time. On keeping, it is found that the broth loses 
most of its toxic properties : this old toxin Ehrlich calls 
toxoid. It is not quite without physiological action, inasmuch 
as, subcutaneously injected, it produces a local lesion and 
wasting of the body. Ehrlich considers that the toxoid is a 
different body from the toxin which produces the acute 
symptoms of diphtheria poisoning, and that the toxoid is, at 
any rate, one, if not the chief, of the active agents producing the 
antitoxin. 

This change in the fresh diphtheria toxin may be illustrated 
as follows : 

Using only one manufacture of toxic broth for all the ex- 
periments, it may be found that, when fresh, one immunity 
unit of serum would neutralize, say a c. c. of toxic broth con- 
taining /? toxic units. If the toxic broth be old, one immunity 
unit will still be neutralized by a. c. c. of the broth, but the 
number of toxic units in this broth will be found to be not 
/?, but — x: that is, although the same quantity of anti- 
toxin is required to neutralize both the fresh and the old 
broth, yet the old broth contains a diminished number of toxic 
units. 

Ehrich therefore considers .that the toxin consists of two 
groups — the toxophore (toxin-bearing) group, and the hapto- 
phore (binding) group (Fig. 60) ; that the toxophore group 
somewhat rapidly degenerates, and leaves eventually only the 
haptophore group, which would be equal to the toxoid. In 
the action of the toxin it is the haptophore group which unites 
with the elements of the cell with which it has affinity : hence 
the name haptophore (anrsiv, to bind). 

If the amount of antitoxic serum injected with the 
toxin is not sufficient to neutralize it, the animal suffers from 
symptoms which are proportional to the amount of toxin not 
neutralized, and which may end in death; and this result is 
observed, even though an additional amount of antitoxin be 
immediately injected subcutaneously. If, in rabbits, the toxin 
be injected intravenously, and immediately afterwards a cer- 



ANTITOXINS 181 

tain amount of antitoxin is also injected intravenously, the 
animal may be saved; but if an interval of seven or 
eight minutes is allowed to elapse between the injections, the 
animal dies unless a very large dose of antitoxin is given. 
After a longer period, the injection of antitoxin does not 
counteract the poison. 

These results have been confirmed by many observers, and 
show that, for a time, the toxin is free in the blood and capable 
of being neutralized by the antitoxin ; that after a short period 
it becomes combined with the elements of the body, and is 
thus with difficulty neutralized. After a still longer period, 
it has produced its effect on the body, and no neutralization by 
antitoxin is possible. 

These facts demonstrate the rationale of the treatment by 
antitoxin of diphtheria as it occurs in man. Large doses have 
to be given, and it is only because, in the natural disease, 
toxins are formed slowly, that it is possible in the early stages 
of the disease to inject sufficient antitoxin to counteract the 
effects of the disease. When sufficient toxin has combined 
with the tissues to produce a fatal result, this cannot be pre- 
vented by the injection of even large doses of antitoxin, al- 
though this will prevent the action of any more toxin, or its 
formation by the bacillus. 

The question whether this neutralization is a purely chemical 
one, or whether it requires the medium of the cells of the body, 
has been much discussed. 

The neutralization of the toxin by antitoxin does not need 
the medium of the body in order to take place. 

Calmette, in his experiments with cobra poison, showed 
that although this was not apparently affected by an ex- 
posure to 68° C. for ten minutes, the antitoxin was com- 
pletely destroyed by the same treatment. In this way the 
effect of antitoxin could be removed in a mixture with 
toxin, in the case of there being no chemical neutralization 
of the two substances. Calmette found that mixtures of 
cobra poison and antitoxin, which produced no symptoms 
when injected into a rabbit, were fatal if they were previously 
heated for ten minutes at the temperature mentioned. It 



1 82 INFECTION 

will be noted, however, that Calmette allowed the antitoxin 
to act on the toxin for only ten minutes before subjecting* 
the mixture to heat. The time was, perhaps, too short for 
a complete chemical union between two bodies of such 
complex molecular construction as the toxin and anti- 
toxin. 

The poison of the bacillus pyocyaneus is not destroyed by 
boiling, but its antitoxin is. A heated mixture of the two 
substances causes death when injected, a similar mixture un- 
heated producing no symptoms (Wassermann). 

Similar experiments have been done with the antitoxin of 
diphtheria, and with the same results. The separation of the 
toxin and antitoxin was made by heat, the toxin being destroyed 
at a temperature of 6o° C, whereas the antitoxin is not 
destroyed by heating to jo° C, although it loses its power if 
heated to higher temperatures. 

On the other hand, Kanthack showed that cobra antitoxin 
counteracted the influence of cobra poison in preventing the 
coagulation of shed blood, and the hemolytic action of cobra 
poison upon blood is also prevented by antitoxin in vitro 
(Stephens and Meyers). Ehrlich also showed that anti- 
ricin prevented the precipitation of the corpuscles in defibri- 
nated blood, one of the characteristic actions of ricin. As 
C. J. Martin and Cherry have pointed out, in these experiments 
in which neutralization of the toxin by antitoxin outside the 
body has not occurred, the element of time has not been 
sufficiently taken into account. These observers utilized the 
method depending on the different behavior of the toxin and 
antitoxin in passing through a porcelain filter, coated with a 
film of gelatin. The toxin passes through, while the anti- 
toxin does not. In a mixture, therefore, they could be 
separated by means of this filter, provided they had not 
chemically combined. 

In the case of diphtheria toxin and antitoxin, when the 
mixture was kept for two hours at 30 C. and then filtered, it 
was found that the filtrate had no toxic action, showing that 
the toxin had remained behind; whereas, when not so< kept, 
the filtrate was toxic. Experimenting with snake-venom and 



ANTITOXIN FORMATION 183 

antivenene, it was found that, if sufficient time were allowed 
for the toxin and antitoxin to react upon each other, the 
same results were obtained as in the case of the diphtheria 
products. 

These results conclusively show that the neutralization of 
the toxin by antitoxin, although slow, is essentially a chemical 
process, and explain some of the facts previously mentioned 
with regard to the interaction of these two bodies. Thus it 
was seen that the small amount of antitoxin requisite to neu- 
tralize a large amount of toxin, when these were mixed before 
injection into the body, was quite inadequate to prevent death 
if the toxin and antitoxin were injected subcutaneously in 
different spots. In this latter case, the toxin is absorbed, com- 
bines with the tissues on which it acts, and produces its poi- 
sonous effects before it is neutralized by the antitoxin. Al- 
though some of the toxin is neutralized, yet sufficient is left to 
produce a fatal result. 

The amount of antitoxin requisite to neutralize the toxin, 
when these are injected subcutaneously at different spots, is 
from twenty to a hundred times larger than the amount of anti- 
toxin required when the two substances are mixed together 
before injection. 

(b) Theory of Antitoxin Formation and Action. — Ehrlich 
supposes that the protoplasm of the cell has different elements 
possessing affinity, not only for toxins of various kinds, but 
also for the elements of food. These parts of the cell he refers 
to as side-chains, and represents diagrammatically as projec- 
tions from the cell of varying shapes, as in the accompanying 
figures (Figs. 60 and 61). The toxin unites itself to a side- 
chain by means of its haptophore group, and then, mainly by its 
toxophore group, affects the vitality of the cell. The toxin 
may kill the cell or produce alterations in the structure, but it 
also leads, under certain conditions, to the formation of 
numerous other side-chains, which are antagonistic to it. 
These side-chains express the reaction of the cell to the action 
of the toxin, and eventually become liberated in the blood as 
antitoxin. In Ehrlich's words — " Antitoxins represent noth- 
ing more than side-chains reproduced in excess during re- 



r 8 4 INFECTION 

generation, and therefore pushed off from the protoplasm, and 
so coming to exist in a free state." 




Fig. 60. — Diagram illustrating Ehrlich's theory of side-chains of cells 
combining with toxin molecules, and the formation of anti-bodies 
(Ehrlich). 

A is the diagram of a cell with side-chains projecting from its surface of various 
shapes, each adapted to combine with a particular toxin molecule or food element. 

B is an animal cell, in which one of the side-chains has combined with a toxin mole- 
cule composed of haptophore (<z) and toxophore (b) parts. The side-chain is com- 
monly called a "receptor." 

C represents the diagram of a cell, with the receptors of which numerous toxin- 
molecules have combined. 

D is the diagram of a cell in which, following the combination of the toxin mole- 
cules with the receptors, there is the formation of new side-chains (c)» which, set free 
in the blood, constitute the antitoxin. 



ANTITOXIN FORMATION 185 

As regards the combination of the toxin with the proto- 
plasm of the cell, there is much evidence of this in the selective 
affinity of toxins for certain tissues. The action of strychnin, 
for example, in producing convulsions, is due to the direct effect 
upon, and, no doubt, combination of the alkaloid with the 
motor cells of the spinal cord. In the guinea-pig and, probably, 
in man, there is evidence that the toxin of tetanus is almost 
solely contained in the central nervous system combined with 
the tetanophilc atom groups, whereas, in rabbits, it is contained 
in the other organs as well. 

In the case of toxins such as those of anthrax, typhoid, 
-cholera, in which there is not any evidence of any special action 
on tissues, it must be supposed that the general effect is due 
to a more or less universal combination of the toxin with the 
elements of the body. 

The formation of antitoxin is not so readily discussed. The 
antitoxin is, probably, not a new formation, or, at any rate, 
not a body widely separated, chemically, from the elements of 
the body. It is, like the toxin, closely associated with the 
proteids, and may, indeed, be itself a proteid body. 

There is evidence that, in some cases, the antitoxin exists 
normally in the blood. Thus, the serum of some normal horses 
contains a small quantity of an antitoxin which counteracts the 
diphtheria poison, and proteid substances have been obtained 
from different parts of the body, notably the spleen, which, 
to some extent, counteracted the action of anthrax (Hankin). 
That the formation of antitoxin " is not a purposeful, intelli- 
gently directed process," is shown by the remarkable results 
observed in the reaction of the blood against the injection of 
certain non-poisonous substances. 

Thus, rennin (the rennet ferment), when injected into the 
horse, leads to the formation of a large quantity of antirennin, 
the action of which, outside the body, is to stop the activity 
of the ferment, and this formation takes place in proportion 
to the amount of ferment injected. The blood serum of the 
normal horse contains a small quantity of this antirennin 
(Morgenroth). 

Moreover, Bordet has shown that in animals injected with 



1 86 INFECTION 

milk, the blood serum acquires the property of coagulating the 
milk of the animal from which the milk was obtained. Thus, 
if goats' milk were used, goats' milk alone would be coagulated, 
and not human or cows' milk. A similar reaction in the blood 
is obtained by injecting the serum of different animals or the 
white of egg. A reaction takes place, leading to> the formation 
of substances (coagulins), which precipitate only the form of 
albumin which has been injected. 

These results are extremely important in explaining the 
formation of antitoxin, which must be considered as a substance 
not new to the body, but as little removed from the proteid 
substances of the body, or, at any rate, as closely connected with 
the processes of nutrition in the cell protoplasm. 

2. Agglutinins and Bacteriolysins (Antimicrobic Subr 
stances). — The properties of an antimicrobic serum are dif- 
ferent from those of an antitoxic serum. An antimicrobic serum 
protects an animal against the invasion of the particular micro- 
organism used in its preparation, but will not protect against the 
action of the toxin of the micro-organism, or, at any rate, only 
to a very slight extent, so that it would appear that, in some 
instances, the antitoxic property and the antimicrobic property 
are produced by different actions of the micro-organism and 
its toxin; whereas, in some instances, as in those just con- 
sidered, the toxin of the micro-organism produces, by its re- 
action, a serum which is both antitoxic and antimicrobic. 

The subject has been, as yet, only touched upon in regard 
to this investigation, and inasmuch as different animals react 
differently to the same micro-organism, it may be found that, 
in these cases, it is partly a question of one animal forming 
an antimicrobic serum, and another forming an antitoxic 
serum. 

The chief antimicrobic sera which have been prepared, are 
the antityphoid, anticholera, antiplague, antipneumococcic, and 
antistreptococcic (Marmorek's serum). A true antitoxic 
cholera serum has, however, been prepared, as well as, it is 
said, for plague and for tuberculosis. 

The preparation of " antimicrobic " serum is illustrated by 
Pfeiffer's experiments with cholera and typhoid. 



AGGLUTININS 187 

Pfeiffer's Specific Serum Reaction for Cholera and Typhoid 
Fever. — The diluted blood serum of guinea-pigs highly im- 
munized against the cholera vibrio, when inserted with a viru- 
lent vibrio into the peritoneal cavity of another guinea-pig, 
kills the vibrio, causing the vibrios to clump together (agglu- 
tination), and finally disintegrating them (bacteriolysis). 

Guinea-pigs were made highly immune by treating them at 
first with a subcutaneous injection of a culture of the vibrio, 
killed with chloroform. After ten to fourteen days, the animal 
received very small and increasing doses into the peritoneal 
cavity of an agar culture of a virulent vibrio, twenty hours old. 
The symptoms were allowed to abate before a fresh injection 
was made. After this treatment the serum was obtained from 
the blood, and preserved by adding 0.5 per cent, phenol. If 
10 to 30 mgm. of this serum, mixed with one loopful of an 
agar culture of the vibrio in 1 c. c of broth, were placed in the 
peritoneal cavity of a guinea-pig weighing 200 grams, the 
vibrio would become immotile in twenty minutes, and finally 
disintegrate. 

This is a specific reaction occurring between the cholera 
vibrio and anticholera serum, and has been found to be given 
by all varieties of cholera vibrio, obtained from many sources. 
A similar reaction occurs with the typhoid bacillus and anti- 
typhoid serum prepared in the same way. 

Gruber and Durham utilized a simpler method of immuniz- 
ing guinea-pigs, and found that the reaction could be obtained 
outside the body in tubes, and could be watched occurring 
under the microscope. This is known as the serum reaction of 
cholera and typhoid fever. 

Thus, if 2 to 4 mgm. of an agar culture are mixed in 
0.5 c. c. of broth, and 10 mgm. of immunized serum dissolved 
in 0.5 c. c. of broth, and the two liquids mixed and placed 
in the incubator at 37 C, it is observed that the micro- 
organisms first begin to clump together; they then cease 
movement, and. in some instances, undergo disintegration. 
If the reaction is done in a tube, the micro-organisms sink 
to the bottom. The clumping and cessation of movement 
occupy ten to fifteen minutes, and the micro-organisms sink 



1 88 INFECTION 

in about one hour's sedimentation, although this may take 
longer, 

Pfeiffer found that the serum of convalescent cholera 
patients contained the same substances as the serum of the 
immunized guinea-pigs, and in typhoid fever the serum 
possesses antimicrobic properties, both during the occurrence 
of the disease and for some time afterwards. The reaction 
in typhoid fever is sometimes referred to as Widal's reaction. 
It is used for the purposes of diagnosis of the disease, and is 
specific. 

Typhoid Serum Reaction. — This may be performed in two 
ways, either under the microscope or in small tubes. The 
serum is obtained from the patient by receiving the blood 
into capillary pipettes, which are then sealed at each end. 
After the blood is coagulated, the ends of the tube are broken 
off", and the small column of clot and serum blown into a 
sterilized tube. It is then diluted and mixed with a twenty- 
four-hour-old broth culture of the typhoid bacillus in varying 
dilutions— i in 30, 1 in 50, and 1 in 100 or less. If a portion 
of the liquid is placed under the microscope in a hanging 
drop, within thirty minutes to an hour, or less, all the bacilli 
are clumped together (agglutination), and are motion- 
less. This is a positive and complete reaction. A partial 
reaction, however, is frequently obtained, where there is more 
or less complete clumping, and a partial immotility. The 
reaction is specific, and occurs only between the typhoid serum 
and the typhoid bacillus. 

Durham has shown that the reactions of other allied micro- 
organisms, the bacillus coli communis and Gaertner's bacillus, 
overlap the reaction of the typhoid bacillus. Thus it may be 
found that the serum from an individual case will give the 
reaction with all dilutions up to 1 in 200 with the typhoid 
bacillus ; a reaction up to dilutions of 1 in 100 with Gaertner's 
bacillus ; and a reaction with the bacillus coli communis 
in solutions not so dilute. These results express the close 
relation which exists between these three micro-organisms, 
but they do not vitiate the diagnostic value of the typhoid 
serum reaction as applied clinically; and as an aid to the 



AGGLUTININS 



189 



diagnosis of typhoid fever, it is, as a rule, sufficient to ob- 
serve the effects in dilutions of 1 in 30 or 1 in 50, and 1 in 
100. 

Agglutination is not observed solely in the instances which 
have been mentioned : it has been observed in Malta fever and 
in glanders as well. 

The reactions which have been discussed are not so simple 
as it would appear at first. Pfeiffer thought that the antimi- 
crobic substance in the serum became bactericidal only in the 








Fig. 61. — Diagram showing antitoxin formation (Ehrlich). 

E represents a portion of the cell with numerous side-chains, some of which are 
being set free in the blood. This represents the continuous formation of antitoxin 
when no more toxin is present to be combined with the cell. 

F is a diagram showing what occurs when toxin is injected into an animal in whose 
blood there is free antitoxin. The toxin molecules never reach the cell, but combine 
in the blood stream with the free antitoxin. 

presence of living protoplasm. But it has been shown that, 
not only the peritoneal fluid, but normal serum, can take the 
place of the living cell; that is, that the specific serum reaction 
for cholera is observed outside the body, when a culture of 
the vibrio, anticholera serum, and fresh serum from a normal 
guinea-pig, are mixed together. 

For this reaction to occur, there is necessary the body in 
the anticholera serum, and another body which is present in 
the normal serum. The former Ehrlich calls the connecting 
link or immune body; the latter he calls the complement or 



190 



INFECTION 



addimcnt, and his notion of the process is illustrated in the 
figure (Fig 62). 

3. Coagulins and Precipitins. — These are substances which 
are formed in the animal body when solutions or mixtures of 
proteids are injected. Thus the injection of milk leads to the 
presence in the serum of a substance which produces coagula- 
tion in the kind of milk used, and the reaction for the different 
kinds of milk (human, goat's, and cow's) is specific. There are 
also specific coagulins and precipitins for serum, when the 
serum of one animal is injected into another. This does not 
hold good for all animals. Thus guinea-pigs do not yield a 
specific serum when rabbits' blood is injected into' them, nor 
do pigeons yield a specific coagulin for fowls' blood. Anti- 
bodies have also been produced by the injection of egg-albumen, 
globulin from sheep's and ox's blood and peptone. Although 
the subject is not yet worked out, yet it appears that the specific 
anti-bodies are allied when obtained from closely related races. 
Thus the specific precipitin of the blood of the higher apes 
reacts to some extent with human serum. ' 

4. Cytotoxins. — Cytotoxins are anti-bodies which are pro- 
duced by the injection into' the animal body of cells. The 
best known of these are the hemolysins, which are specific 
substances dissolving the hemoglobin from the blood cor- 
puscles; but to the same group belong the bacteriolysins, 
which dissolve bacteria and are bactericidal substances, and 
certain cytotoxins produced by the injection of spermatozoa 
(spermatoxin), of ciliated epithelium (trichotoxin), of leuko- 
cytes (leukotoxin or leukocidin), of kidney substance (nephro- 
toxin), of liver substance (hepatotoxin) ; and similar sub- 
stances produced by the injection of pancreas and of the supra- 
renal bodies. 

Injection of spermatozoa into the peritoneal cavity confers 
on the serum of the animal used the property of causing cessa- 
tion of movement in, and ultimately destroying, the variety 
of spermatozoa used, whether those of the bull, the rabbit, 
or of man. The property depends on two substances, as in 
the case of hemolysins, namely, of an immune body (fixateur), 
and of a complement or alexin (cytase). Rabbits or ducks 



IMMUNITY: SUMMARY 



191 



treated by injections of dogs' liver yield a serum which, in- 
jected into healthy dogs, kills them with the appearances and 
symptoms of acute yellow atrophy of the liver. A similar 
effect has been observed in the kidney tubules from the injec- 
tion of nephrotoxin. 

Hemolysins are discussed in Chapter XII. 



Summary. — The facts which have been brought forward in 
the preceding chapters to some extent aid in the explanation 



b... 





Fig. 62. 

A represents the periphery of an animal cell with a single receptor, which 
has combined with a complement colored black by means of a connecting link 
or immune body. Without this immune body the complement cannot become 
attached to the cell. 

B represents an animal cell in which the same has occurred, that is, the 
receptor is joined to the immune body, which is connected with a "ferment 
toxic group " and a complement. 

of both natural and acquired immunity. Two phenomena 
stand out as the result of the investigation of these subjects : 
the occurrence of phagocytosis and the presence in the blood 
and tissues in artificially produced immunity of substances 
which are antagonistic to the invadingmicro-organisms. Path- 
ogenic bacteria, when they enter the immune animal, are not 
passed out by the mucous membranes or excretory organs, but 
are destroyed in the body, and it is the mechanism of their 



192 INFECTION 

destruction — an essentially vital act — which is the main 
problem in the question of immunity. The phagocytes are 
divided by Metchnikoff into macrophages and microphages 
(p. 32). Each of these contains a specific cytase or ferment, 
macrocytase and microcytase, the former of which acts specially 
on elements derived from animals, the latter chiefly on bacteria. 
The macrophages are those which take up red corpuscles and 
spermatozoa, but they may also take up the bacteria of leprosy, 
tuberculosis, and actinomycosis, as well as the malarial or- 
ganism. The microphages are almost solely occupied in tak- 
ing up the pathogenic bacteria. The cytases are destroyed 
at a temperature of 55 to 56° C, and correspond to the sub- 
stance called complement by Ehrlich, and alexin by Buchner. 
According to Metchnikoff, it is by the disintegration or plas- 
molysis of the phagocytes that the cytases which they contain 
are set free, and these confer on the serum its hemolytic and 
bactericidal properties. The microphages digest bacteria by 
means of the microcytase, and this action may go on in the 
plasma when the microphages set free their contained ferment. 

The properties of the serum of a naturally immune animal 
do not explain its immunity. The pigeon, for example, is 
refractory to the influenza bacillus, but its blood is a good cul- 
ture medium for the bacterium. The dog is refractory to the 
anthrax bacillus, while its serum is not bactericidal. Other 
examples might be given showing that the effect of the serum 
of a naturally immune animal does not explain its immunity. 
This immunity is due, according to Metchnikoff, to the action 
of the phagocytes, by themselves for the most part in natural 
immunity, and with the aid of immune bodies or anti-bodies 
(fixateurs) in artificial immunity. The origin of the immune 
bodies is still a matter of discussion. Metchnikoff, on the one 
hand, believes that their main source of origin is the phago- 
cytes themselves; while Ehrlich believes that the cell most 
affected by the toxin produces the antitoxin. 



CHAPTER VII 

ON THE DEGENERATION AND REGENERATION OF 
CELLS AND TISSUES 

The degeneration of cells and tissues is a frequent occurrence 
in disease, both acute and chronic. It is due to both local and 
general causes. Of the local causes may be mentioned — ( I ) The 
local action of a poison, such as occurs in an infective focus 
(inflammatory area) ; (2) a diminution in the supply of nutri- 
ment; and (3) the influence of disease of the nervous system. 

The most potent cause of cell and tissue degeneration is 
the circulation of a poison in the body, and such poisons may 
produce a widespread degeneration. Tissue degeneration may 
also follow what may be called nutritional changes, more 
particularly the diminished supply of food through defects of 
the digestive organs or of the local blood supply. The nutri- 
tion of the cell is a very delicate process, and one which 
is readily disorganized by the character of the food supplied 
to it; and, in the case of solid and secretory organs, by the 
varying influence of the nervous system on its activity. As 
regards the food supplied to the cell, two factors must be 
borne in mind: the character of the food brought to the cell 
may be unsuitable, or the blood vessels supplying the cell may 
be so altered by disease as to bring insufficient nourishment, 
even of a suitable character. 

The influence of the nervous system on the vitality of the 
cell is difficult to gauge, but may be evidenced in two dif- 
ferent ways. Thus the nerve supply of an excretory organ 
being disorganized or abolished, the cells of the organ are 
not brought into activity as they normally are by reflex in- 
fluence. The cell therefore becomes disorganized, and tends 
13 193 



i 94 DEGENERATION AND REGENERATION OF CELLS, ETC. 

to degenerate. Again, the nerve supply to a voluntary muscle 
may be diseased, and so lead to inactivity of the muscle fiber, 
thus leading to degeneration. 

The cell is capable of certain changes in health, such as 
the absorption of nutrient material, the assimilation of such 
material, the discharge of products of activity of the cell, and 
the reproductive changes which are evidenced in division of the 
cell. In disease similar changes occur, but are modified. The 
assimilation of nutrient material diminishes with degeneration 
of the cell, and in the early stages the products of cell activity 
show an exaggeration of the normal secretion. As degenera- 
tion proceeds, however, secretion diminishes and finally ceases. 
The structure of the cell is altered, and finally is completely lost. 
The normal cell (Fig. 63) consists of a cytoplasm which 
shows a reticulum of plastin; the nucleus also contains a retic- 
ulum, which undergoes various changes in the degeneration of 
the cell. The composition of a normal cell is as follows : it con- 
tains proteid substances, such as nucleo- 
„.-*-n albumin, of which the plastin consists, 
, and globulins. The amount of albumin 
present is small, and albumoses, which 
~P are the products of digestion in the 
alimentary tract, are absent from the 
normal cell. The vacuoles of the cell 
Fig. 63^D agram of conta in a watery fluid, which changes 
a cell, the protoplasm of in reaction from alkaline to acid during 

s^ongioplasm^nd'hyalo- the activit y of the cell. The nucleus 
plasm. consists of chromatin (plastin) and 

cie/s; w^nuSfiofS! (Quafn's achromatin, while the nuclear matrix 
Anatomy) is rich in proteids. From the cells of 

healthy organs the proteid substances above mentioned can be 
extracted. The most characteristic proteid of the cell must be 
considered as the nucleo-albumin, inasmuch as this does not 
exist in solution in any fluid of the body. 

The secretion of cells and the substances discharged from 
them vary considerably according to the specialization of the 
cell, but the substances discharged are not the same as those 
forming the nutriment of the cell. Ferments are discharged 




NUTRITION OF THE CELL 195 

from cells — chiefly of the glands concerned with digestion 
— and are manufactured by the cell. Thus there is the 
ptyalin of the saliva, the pepsin of the gastric juice, and the 
trypsin of the pancreatic juice. This secretion of ferments by 
the cell is, however, only an emphasized property of all cells. 
It is probable that the cell digests its nutriment by means of 
ferments, and it is true that an amylolytic ferment can be ex- 
tracted from most tissues, and a proteolytic from many. 

The proteid substances which are brought as nutriment 
to the cell are probably in health always of the same kind; 
from whatever source they are derived, animal or vegetable, 
they are digested in the alimentary tract, and are transformed 
into the proteids of the body by the mucous membrane of 
the intestine. What is called a proteid is, however, neither 
chemically nor physiologically a single substance. Albumins 
and globulins are no doubt of infinite variety, although their 
general chemical reactions and their percentage composition 
may be the same. The cells of the body are adapted to 
receive only one or other form of proteid substance, and it 
has been shown that some forms injected into the body do 
not serve as nutriment to the cell, but produce substances 
foreign to the normal metabolism of the body (p. 190). In 
some instances proteid substances different from those already 
mentioned as constituting part of the cell are formed by the 
cell, and sometimes secreted from it. Thus gelatin is obtained 
by treating with boiling water a substance called collagen 
existing in the white fibers of connective tissue, in bone and 
cartilage. Gelatin is soluble in hot, and insoluble in cold, 
water, and contains no sulphur, unlike ordinary proteids. It 
is digestible by gastric juice, forming substances like albu- 
moses and peptone. The proteid substance in cartilage is 
called chondrogen; it is a mixture of collagen and mucinoid 
substance, and by boiling yields chondrin. which contains 
gelatin. Mucin is a glucosid compound of a proteid with 
animal gum found in the secretion of mucous membranes, in 
synovia and saliva, and in bile. It is a viscid, slimy, 
tenacious substance, soluble in dilute alkali, and precipitated 
from solution by acetic acid, the precipitate being insoluble 



I9 6 DEGENERATION AND REGENERATION OF CELLS, ETC. 

in excess of the acid. Colloid substance occurs normally in 
the thyroid gland, and resembles mucin, except that acetic 
acid does not precipitate it. It is found also in tumors of 
the thyroid gland and in ovarian cysts. Other transformed 
proteids resembling mucin are called spermatin, from semen; 
and elastin, from elastic tissue. 

Speaking generally, it may be said that the nature of the 
activity of the diseased cell does not alter in disease as regards 
the substances which it forms. Thus the formation of mucin 
and of colloid substances is frequently observed. This general- 
ization, however, is not correct as far as present knowledge 
goes, inasmuch as one substance is formed in disease which 
is not known to be formed by the normal cell. This is 
lardacein, which is formed in albuminoid degeneration. It is 
a substance colored mahogany-brown by iodin, and so reacts 
like glycogen, but it is nitrogenous, and has the percentage 
composition of a proteid. It is insoluble in water, alcohol, 
and ether, dilute acids, and alkalies. Strong alkalies dissolve 
it, and so after a long time does the gastric juice. 

The following forms of degeneration of cells and tissues 
will be considered: i. Cloudy Swelling; 2. Fatty Degenera- 
tion; 3. Albuminoid Degeneration, Zenker's Degeneration; 
4. Mucinoid Degeneration; 5. Colloid Degeneration; 6. 
Dropsical Degeneration; 7. Atrophy; 8. Necrosis; 9. Fibrosis. 

I. Cloudy Swelling (Fig. 64) .- — This is a change seen in the 
heart muscle and the cells of the kidneys and liver. The muscle 
fibers or the cells become enlarged, do not stain readily with 
dyes, and show in the protoplasm numerous small granules 
which are stained brown, but not black, by osmic acid, and are 
in the fresh condition of the cell soluble in acetic acid and in- 
soluble in alcohol and ether. In addition to these changes the 
muscle fiber of the heart shows a longitudinal fibrillation, which 
is most marked after treating with osmic acid. Cloudy swelling 
is observed in infective diseases, such as rheumatic fever, ty- 
phoid fever, pneumonia, scarlet fever, and diphtheria. It has 
been ascribed to the prolonged high temperature which exists 
in some of these cases. Without denying that the prolonged 



CLOUDY SWELLING 



197 



high temperature of the body may inflict a damage on the cells 
of organs, and so lead to degeneration, it may be said that 
cloudy swelling occurs in cases in which a high temperature 
does not exist for any length of time, as, for example, in cases 
of diphtheria, where the temperature may be low or not raised 
for long at all above the normal, and yet toxemia persists and 
cloudy swelling is found after death. Cloudy swelling is 




Fig. 64. — Cloudy swelling of the liver. 

The liver cells are seen enlarged and studded throughout with fine 
granules of a uniform size : the nuclei are distinct. These granules are not 
fat, as they are not soluble in ether. They dissolve, however, or become 
transparent in acetic acid. 

closely related to fatty degeneration, and in the same cell are to 
be seen the granules which are characteristic of cloudy swelling, 
and others, soluble in ether and stained black with osmic acid, 
which are fat granules. Both cloudy swelling and this form of 
fatty degeneration are toxic in origin, being due to the direct 
effect of a poison on the cell. 



2. Fatty Degeneration. — The fatty changes which occur in 
the body are divided into two classes. In fatty infiltration or 



198 DEGENERATION AND REGENERATION OF CELLS, ETC. 

lipomatosis (obesity, adiposis), there is an increase in the nor- 
mal fat in the localities in which it exists, both beneath the 
skin, in the abdomen, and round the heart (Fig. 65). This 
change is pathologically related to fatty infiltration of the liver, 
which normally contains some fat. This is increased in cer- 
tain conditions — for example, in animals that are suckling and 
in fishes after spawning. 

Fatty degeneration is the change to be discussed here. It 
differs from fatty infiltration pathologically in the fact that 




Fig. 65. — Fatty infiltration of the heart. 

A section of the cardiac muscle under a low power, stained with osmic 
acid. 

The muscle fibers are seen cut, mainly longitudinally, showing here and 
there blood vessels. The chief characters of the specimen are the masses 
of fat cells, which are stained black by osmic acid. In the upper part of the 
figure these cells are in large groups in a strand of connective tissue. 

In the lower part of the figure the fat cells are seen penetrating the 
bundles of fibers. 

the globules of fat are formed by the protoplasm of the cell, 
and not brought to it as nutriment. It is the most common 
of all the degenerations occurring in the cells of the body. 
All the cells of the body utilize fat in their metabolism. When 
fat accumulates in the cell it is due either to the fact that the 
fat brought to it is not utilized after absorption, or that the fat 



FATTY DEGENERATION i 99 

manufactured by the cell is not discharged. From this point 
of view fatty degeneration may in its pathological processes 
come into line with fatty infiltration, in which the main fea- 
ture is that the fat brought to the cell is stored in it without 
being used for the needs of the body. 

The changes observed in the cells in fatty degeneration are 
characteristic. In the heart muscle (Fig. 66) minute globules 
are seen which are stained black by osmic acid, and which run 
longitudinally in the fiber, commonly in lines. The faint trans- 
verse striation of the fiber is lost as the granules increase in 
number. The nucleus degenerates and disappears, and in the 
advanced stage no structure of the fiber is observed, but only a 
collection of fat granules. In the cells of the liver (Fig. 67) a 
similar change occurs, the globules of fat being, however, of 
varying size, but their accumulation leads, as in the muscle fiber, 
to the eventual destruction of the cell. In the kidney (Fig. 68) 
the epithelium of the convoluted tubes is mainly affected, and 
here similar changes are seen to those occurring in the liver cell. 
The cells of the glands of the body and of the nervous system 
undergo the same changes, which need not be further described. 

The fat of the body consists of tri-palmitin, tri-stearin, 
and tri-olein, and shows the same composition whether ob- 
tained from normal subcutaneous fat, from the fat of lipo- 
matosis or fatty infiltration, or from the fat in fatty degenera- 
tion. The organism manufactures fat from proteid substances 
and by the agency of cells. Dead proteids cannot of themselves 
be transformed into fat, although the contrary has been stated 
to be the case. The transformation under certain conditions 
of dead bodies into adipocere, which is a kind of fat, is at first 
sight an instance of the transformation of proteids into fat 
by a chemical process. It is, however, probable that the trans- 
formation occurs by means of living organisms present in 
water in which the body lies, and not by any cell-transformation 
of the proteids into fat. Again, portions of recently removed 
organs implanted in the abdomen of a living animal undergo 
fatty degeneration, but this fatty degeneration does not affect 
the cells of the implanted organ, but is seen in the leukocytes 
which invade the organ in great numbers. 



2oo DEGENERATION AND REGENERATION OF CELLS, ETC. 




Fig. 66. — Fatty degeneration of the heart. 

The muscle fibers are stained by osmic acid. The fibers show longitudinal stria- 
tion, and occupying most of the fibers are globules stained black by osmic acid. These 
are particles of fat. 

The nuclei are not shown, as the specimen was not counter-stained. 




Fig. 67. — Fatty degeneration of the liver under a low power, 
stained by osmic acid. 

A transverse section of a lobule is shown with the central vein distended 
with blood, and connected with the distended hepatic capillaries. There is, 
therefore, some venous congestion. 

The main characteristic of the specimen is, however, the presence in the 
cells, more particularly at the periphery of the lobule, of globules of fat, which 
in most instances show as black masses; in some, however, where the fat has 
fallen out and disappeared, round spaces only are seen. 

Towards the center of the lobule the fat particles are less numerous. 



FATTY DEGENERATION 201 

Fatty degeneration is the result of a damage to the 
functional activity of the cell, provided that the damage is not 
sufficiently great to kill the cell outright. This damage to 
the cell ending in fatty degeneration may arise from three 
causes : 

I. A deficient supply of nutriment to the cell, due either 
to a defect in the blood supply of the part or to a diminution 




Fig. 68.— Fatty degeneration of the kidney. 

A section of the kidney is shown stained by osmic acid, and not counter- 
stained. The tubules shown are chiefly straight tubules, and the cells are 
stained almost black by the acid, owing to the extreme fatty degeneration 
of the protoplasm. From a case of acute infective disease, in which the 
liver and heart also showed advanced fatty degeneration. 

in the total amount of oxygen taken into the body or supplied 
to the part. 

2. There may be a defect in the nerve supply to the tissue, 
as is seen in the fatty degeneration occurring in peripheral 
neuritis and in paralysis due to disease of the central nervous 
system. Of like nature is the fatty degeneration occurring 
in disused muscles. The removal of nervous influence is prob- 
ably also responsible for the degeneration occurring in certain 



202 DEGENERATION AND REGENERATION OF CELLS, ETC. 

glands in the body, more particularly in those that have a 
secretion. 

3, One of the most potent causes of fatty degeneration is 
the action of poisons. In some instances these causes act 
together, a defect in the circulation or in the nerve supply 
acting with a toxic cause. 

1. Fatty Degeneration Due to a Defective Supply of Nutri- 
ment to the Cell. — In this case there are two conditions to be 
considered. In one the arterial supply to the part is diminished 
by disease of the vessel, whereby the supply not only of liquid 
nourishment, but of oxygen, varies greatly from the normal. 
In the other there is no arterial disease, but the supply of oxy- 
gen is deficient. The following examples may be given of fatty 
degeneration due mainly to a diminished supply of arterial 
blood. In disease of the coronary arteries of the heart, the 
muscle fibers show in many instances fatty degeneration, which 
is frequently very irregularly distributed. The kidney cortex, 
in cases of arterio-sclerosis, shows a similar change. In ad- 
vanced albuminoid disease of the liver and kidneys, areas of 
fatty degeneration are frequently observed, and the change is 
no doubt directly to be ascribed to a diminished supply of 
blood, due to the great narrowing of the vessels of the organ. 
The fatty areas which occur in cirrhosis of the liver and in 
granular contracted kidney are to be ascribed to the same main 
cause, the diminished blood supply in this case being due to the 
contracting bands of fibrous tissue. After parturition, and 
during involution of the uterus, many of the muscle fibers 
undergo fatty degeneration, disappearing as the organ regains 
its normal size. This change is to be ascribed to the diminished 
blood supply to the organ, which occurs immediately after 
the contraction of the uterus following parturition. New 
growths, in which the blood supply is deficient, as in scirrhus 
and other forms of carcinoma, frequently show areas of fatty 
degeneration of the cells. 

To the diminution in the amount of oxygen supplied to 
the tissue has been ascribed a large role in the production of 
fatty degeneration. This appears to be the explanation of 



FATTY DEGENERATION 203 

the fatty changes which are observed in the heart, arteries, 
liver, kidneys, and other organs in the profound anemias, more 
particularly pernicious anemia. To a much less extent similar 
changes are found in chlorosis, secondary anemias, and in 
leukemia. In all these conditions the amount of hemoglobin 
in the blood is diminished, and so a deficient quantity of 
oxygen is carried to the tissues. There is thus a diminished 
metabolic activity in the organs and tissues, and it is to this, 
as well as to the diminished amount of oxygen, that the fatty 
changes are ascribed. The same explanation has been 
offered regarding the fatty changes which occur in old age in 
the lens, the cornea (arcus senilis), cartilage, epithelial tissues 
and the genital organs, as well as that occurring in cachectic 
state, as in malignant disease; but in such cases, besides the 
•diminished functional activity of the cell and the diminished 
amount of oxygen supplied to the tissue, the action of a 
circulating poison cannot be eliminated. The fatty degenera- 
tion which occurs in the liver and kidneys in cases of venous 
stagnation (prolonged passive hyperemia) has been ascribed 
to the diminished arterial blood pressure and the diminished 
amount of oxygen. Thus fatty degeneration is observed in 
r nutmeg "liver, the cells of the periphery of the lobule under- 
going fatty degeneration, while those in the center of the lobule 
undergo atrophy from pressure by the distended capillaries 
(Fig. 73). In the fatty changes in the kidney which are ob- 
served in cases of morbus cordis, a similar explanation has been 
made. Fatty degeneration of the liver is observed in cases of 
pulmonary tuberculosis, and the change has been ascribed to the 
diminished intake of oxygen. In emphysema and chronic bron- 
chitis fatty degeneration of the liver does not occur. In this 
case also the disease of the lungs tends to cause a diminished in- 
take of oxygen, but owing to the fact that the muscles are more 
vigorous than in cases of pulmonary tuberculosis, the respira- 
tory efforts are more energetic, and so sufficient oxygen is 
taken into the body; hence fatty degeneration of the liver does 
not occur. This, however, is only an explanation in part, as in 
pulmonary tuberculosis another factor obtains, namely, the 
circulation of a poison in the body. 



20 4 DEGENERATION AND REGENERATION OF CELLS, ETC. 

2. Fatty Degeneration Due to Disease of the Nervous Sys- 
tem. — It is possible that the removal or disorder of the nervous 
influence which is exerted on the secretory glands may lead to 
the degeneration of their cells. But little, however, is known 
of this subject. The instances of fatty degeneration occur- 
ring in this class are illustrated by the degenerative changes 
taking place in the central nervous system as the result of the 
destruction of the disease of the higher nerve center, or of the 
fibers proceeding from it; and secondly, the similar changes 
which occur in the fibers from disease of the lower nerve center, 
as well as the changes observed in the muscles supplied by 
the nerve fibers (Chapter XIX.). 

Destruction of the cortical nerve centers of the motor area, 
or destruction of the white fibers that run through the internal 
capsule, leads to fatty degeneration of the fibers passing through 
thelbase of the brain and the spinal cord; this extends down- 
wards as far as the lower nerve center. Destruction or disease 
of the spinal cord at one spot leads to fatty degeneration in 
certain tracts, both upwards and downwards. The chemical 
change which occurs in the degenerated fibers effects chiefly 
the lecithin of the white matter. The change is shown by the 
fact that the degenerated fibers are stained black by a mixture 
of osmic acid and Miiller's fluid (Marchi), whereas the normal 
nerve fibers of the spinal cord are not stained black by this 
fluid. Lecithin is a complex body composed of glycero-phos- 
phoric acid, stearic acid, and neurin or cholin. It is not 
known into what bodies lecithin is decomposed during the 
process of degeneration of the fiber, but it has been shown 
that the lecithin is much diminished in the degenerated tracts 
of the spinal cord as compared with the healthy tracts (Mott). 

Destruction of the lower center leads to degeneration of 
the motor fibers attached to it as far as to the muscle. 
Section of the motor nerve below the center leads to degen- 
eration of the fibers as far as the muscle. There is some 
evidence that disease of the lower center, stopping short 
of destruction of the cell, may also lead to degeneration 
of the nerve fibers below, but this degeneration is not com- 
plete and occurs irregularly. Similarly, disease may cause 



FATTY DEGENERATION 205 

degeneration of bundles of fibers in the nerve without the 
whole nerve being affected. In this case only the fibers af- 
fected show degeneration as far as the muscle. When 
degeneration occurs in the fiber from the center to the 
muscle or from a part of the nerve downwards to the muscle, 
it is spoken of as Wallerian degeneration. The essential 




Fig. 69. — Fatty degeneration of voluntary muscle. Stained 
with osmic acid. 

Portions of three voluntary muscle fibers are shown longitudinally. 
The upper and lower are practically normal, while in the center fiber the 
transverse striation is practically lost, and the fiber is occupied by numer- 
ous small and uniform particles of fat, staining black with osmic acid. 

(From a case of degeneration of voluntary muscle in diphtheritic paralysis.) 

feature of this is that the axis cylinder of the nerve fiber 
is degenerated, and fatty degeneration occurs in the muscle 
fiber attached. 

Fatty Degeneration of Voluntary Muscle (Fig. 69) occurs in 
two stages, in the first of which the muscle fiber shows a tend- 
ency to longitudinal fibrillation after staining with osmic acid, 
and to the formation of granules in parts which do not stain 
black with osmic acid. In this stage transverse striation is 
less evident, but is not completely lost. In the second stage 



206 DEGENERATION AND REGENERATION OF CELLS, ETC. 

the transverse striation is lost; numerous small fat granules 
staining deeply with osmic acid appear in the substance of the 
fiber, and eventually the nuclei disappear. 

Fatty degeneration occurs in the voluntary muscles: (i) 
when these fall into disuse; and (2) when they are directly 
affected by disease of the lower nerve centers and of the 
peripheral nerves. 

In disused muscles fatty degeneration is observed, as in the 
muscles round an ankylosed joint, as well as in muscles that 
have been paralyzed by disease of the higher nerve centers. 
This fatty degeneration is very irregular in distribution, and 
is associated with marked atrophy of the majority of the 
fibers. When there is actual disease of the lower nerve center 
or of the peripheral nerves the fatty degeneration of the fiber 
is dependent on the number of nerve fibers which undergo 
Wallerian degeneration. This is seen very obviously in ex- 
perimental diphtheritic palsy, where degeneration of the nerves 
results from the injection of the diphtheria toxin (Chapter 
XIX.). The nerve degeneration is patchy, some of the fibers 
show only a breaking-up of the myelin sheath, others show 
as well degeneration and rupture of the axis cylinder, with a 
subsequent Wallerian degeneration downwards. The muscle 
attached to this partially degenerated nerve shows partial fatty 
degeneration, many fibers being normal while other show de- 
generation in one of the two stages already described (Fig. 
69). Excessive fatty degeneration of the voluntary muscle is 
only seen where the center is extensively destroyed, or in some 
severe cases of peripheral neuritis. 

On what the fatty degeneration of the voluntary muscles 
depends is not quite clear. There are evidently several 
factors which might be supposed to take part in the process. 
The removal of the nervous influence prevents contraction 
of the fiber, and so causes diminution of its metabolic activity. 
This may be the only explanation of the so-called trophic 
influence of the nerve center over the fiber, but, in addition,- 
the influence of the circulation must be considered; damage 
to the vaso-motor nerves producing a disordered circulation, 
and so a diminished or irregular supply of nourishment and 



FATTY DEGENERATION 



207 



oxygen to the muscle fiber. This leads to accumulation of 
the products of the metabolism of the muscle. 

3. Fatty Degeneration Due to the Action of Poisons. — 
Toxic Fatty Degeneration. — The poisons which when intro- 
duced into the body lead to fatty degeneration are divided into 
two classes : ( 1 ) One class includes chemical substances, such 




Fig. 70. — Acute yellow atrophy of the liver. (Stained with hematoxylin.) 

The lobular structure of the organ is lost, only faint indications of the lobules 
being shown by strands of connective tissue. The liver cells are completely degener- 
ated : in parts they are granular, and over the whole of the area they show globules 
of fat, represented in the figure by clear spaces. 

as phosphorus, antimony, arsenic, mercury; chlorate of potas- 
sium, pyrogallic acid, chloroform, ether, iodoform; (2) the 
other, bacterial poisons and the poisons of infective disease. 

To the action of poisons is to be ascribed the widespread 
fatty degeneration which is not uncommonly observed. In 
poisoning by phosphorus, for example, not only is there well- 
marked fatty degeneration of the liver (Fig. 70), kidneys, and 



2o8 DEGENERATION AND REGENERATION OF CELLS, ETC. 

heart, but also of the glands secreting the digestive juices and 
of the voluntary muscles. It has been said that this widespread 
fatty degeneration is due to the diminished amount of oxygen 
which is taken in in phosphorus poisoning. This is probably 
not the sole explanation, and a more potent factor appears 
to be the direct action of the poison on the cell. 

In chronic alcoholic poisoning, fatty degeneration is observed 
more particularly in the heart and liver, sometimes in the 
kidneys, and although this has been ascribed to the diminished 
amount of oxygen supplied to the tissues, yet it may well be 
due to the direct action of the poison on the cell and proto- 
plasm. 

The second class of cases, namely, the fatty degeneration 
occurring in infective disease, more closely concerns the sub- 
ject. In most of these cases the fatty degeneration occurring 
in the liver, kidneys, spleen, heart, and nervous system is pre- 
ceded by cloudy swelling. The change is not due to a high 
body temperature, but to the circulation of a poison which 
directly affects the functional activity of the cell. 

With bacterial poisoning and the poisons of infective 
disease, the fatty degeneration may be general or localized. 
When general, the heart, liver, kidney cortex, and, to some 
extent, the spleen are found affected, the voluntary muscles 
and, to a great extent, the glands secreting the digestive 
juices escaping. In some instances the cells of the central 
nervous system are affected, mainly by those poisons having 
a specific effect on nerve tissue. Widespread fatty degenera- 
tion affecting the internal organs may be found in prolonged 
illness from rheumatic fever, enteric fever, pneumonia, tuber- 
culosis, diphtheria, and scarlet fever. In some instances, how- 
ever, the fatty changes are localized, affecting more particularly 
one organ, such as the heart, the liver, or the kidneys. This 
may be illustrated by the results of the experimental injection 
of bacterial poisons. In the rabbit the injection of the 
diphtheria toxin produces fatty degeneration of the heart 
and, to a less extent, of the liver. In some cases the liver is 
not affected, nor are the kidneys. The voluntary muscles 
show fatty degeneration, but only in proportion to the degree 



ALBUMINOID DEGENERATION 209 

of nerve degeneration. In the cat, besides the nerve degenera- 
tion, a well-marked fatty degeneration of the kidney cortex 
may be produced. The injection of anthrax poison as well as 
of some other bacterial poisons produces a well-marked fatty 
degeneration of the heart, but of no other organ or tissue. 
This local fatty degeneration must therefore be explained, not 
by any general change taking place in the body, such as a 
diminution in the amount of oxygen, but by a specific effect 
of the circulating poison on the tissue for which it has a 
chemical affinity. This, no doubt, is the explanation of the 
fatty changes occurring in the kidney cortex in scarlet fever 
and in some other infective diseases, and these changes may 
be associated, or not, with the phenomena of inflammation. 

In inflammatory or infective foci fatty degeneration is 
observed, affecting not only the leukocytes present in the foci, 
but also the cells of the tissue. This fatty degeneration fre- 
quently ends in death of the cell, so that the process is referred 
to as necrosis (p. 214). There is apparently a wide difference 
between such an infective focus as a whitlow or abscess and 
a caseous tubercle. From the present point of view, however, 
fatty degeneration of the cells is a feature of both, and ends 
in complete destruction of the cell. (See Caseation, p. 219). 

3. Albuminoid Degeneration. — Zenker's Degeneration. — 
Both these are examples of toxic degeneration. Albuminoid 
(amyloid) degeneration (Fig. 71) occurs in chronic suppura- 
tion, especially of bones or joints, in chronic empyema, 
pulmonary tuberculosis, and in syphilis. It has also been 
found in cases of leukemia, malaria, and cancer. It is a 
degeneration affecting the smaller blood vessels and the 
connective tissue, and is observed mainly in the liver, spleen, 
and kidney. It is also seen in the lymph glands, in the 
mucous membrane of the stomach and intestine, the supra- 
renal bodies, and the heart. How the insoluble proteid body 
called lardacein is produced is not known. Lardacein (p. 196) 
consists of hydrogen, oxygen, nitrogen, carbon, and sulphur, 
and has been described as a compound of chondrogen, sulphuric 
acid, and a proteid. It is a degeneration product which is very 
14 



210 DEGENERATION AND REGENERATION OF CELLS, ETC. 

characteristic, and apparently has no relation to the amyloid 
bodies which are found in the prostate and in the nervous 
system in certain conditions. The frequency and- extent of 
albuminoid degeneration have diminished, owing to the im- 
proved treatment of suppurating areas and of syphilis. Organs 
are very variously affected by the degeneration. In individual 




Fig. 71. — Albuminoid disease of the kidney. 

A section of the cortex is shown, in which all the normal structure is 
lost. The clear spaces are tubules from which the epithelium has dropped 
out ; in some of these spaces remains of the epithelium are to be seen. Be- 
tween the tubules there is a great deal of fibrous tissue. 

Four Malpighian corpuscles are shown, in all of which there is a trans- 
lucent area of albuminoid degeneration, with some indications of the nuclei 
of the capillaries which are destroyed. 

instances the liver, spleen, or kidney may alone be affected, 
most frequently, perhaps, the spleen, while the affection of the 
other organs, such as the heart, mucous membranes, and supra- 
renal bodies is only observed in advanced cases. 

Zenker's degeneration (Fig. 72) is a hyaline change occur- 
ring in the voluntary muscles in enteric fever. It is most com- 
monly found in the rectus abdominis, and but little is known of 
the nature of the substance formed. 




MUCIN OID DEGENERATION 



211 



4. Miiclnoid Degeneration. — The physiological production 
of mucin by cells occurs in the epithelial cells of the mucous 
membranes of the body and of the cells of the glands which 
open on the surface of the mucous membranes. This mucin 
formation is a special property of certain cells of the epithelial 
lining. As the result of catarrh or inflammation due to an 




Fig. 72. — Zenker's degeneration of voluntary muscle. 

A longitudinal section of muscle is shown in which in parts the fibers 
show their normal transverse striation, while in other parts there is no 
structure in the fiber to be detected, with the exception that the sarco- 
lemma is intact. 

(From the rectus abdominis in a case of enteric fever.) 

irritant, the mucin formation greatly increases, so that all the 
epithelial cells become mucin-bearing cells. All mucous mem- 
branes may be affected in this manner. Mucin is, how- 
ever, widely distributed in the body, and is present in small 
quantities in connective tissue. The quantity in connective 
tissue is increased in myxedema and in the myxomatous 
stroma of new growths. In the cells of new growths under- 
going degeneration, some of the globules observed consist of 



212 DEGENERATION AND REGENERATION OF CELLS, ETC. 

mucin, and this is another example of the irregular metabolic 
activity of diseased cells. The tenacious substance present 
in ovarian cysts is not mucin, but is closely allied to it (p. 196). 

5. Colloid Degeneration. — Colloid degeneration is observed 
mainly in certain forms of carcinoma, where the cells are 
transformed into a translucent and glistening material. The 
substance formed in colloid carcinoma is supposed to be similar 
to that found in the thyroid gland, but that it is the same 
is not proved. In new growths in the thyroid and in goiter, 
the colloid material is increased in quantity, but this is not 
the same pathological change as the colloid degeneration of the 
cells of carcinoma. 

6. Dropsical Degeneration. — This is really an infiltration of 
the cells by fluid and is observed in inflammatory areas, in 
nerve cells and more particularly in soft neoplasms. The 
droplets of fluid are seen in the nucleus as well as in the proto- 
plasm of the cell, the cell eventually being destroyed. 

7. Atrophy. — By atrophy is meant the diminution of the 
cells of the part without gross signs of degeneration. It 
appears as the result of old age, of the disuse of parts, and of 
circulatory defects. In old age the diminution and disappear- 
ance of the elastic tissue of the skin and bronchial mucous 
membrane is a well-known phenomenon. The fat in many 
instances also disappears, although this may be due to a 
change in the amount of nutriment taken. The atrophy 
which occurs in the internal organs in old age may be 
ascribed to a diminished functional activity. The atrophy of 
the thymus gland in childhood is as yet unexplained, but that 
of the genital organs at the menopause may be ascribed to a 
cessation of function. The main cause of atrophy appears to 
be the diminution or cessation of functional activity, provided 
that no irritant acts on the tissue, and that no infection takes 
place. The following examples will illustrate this point. 
Atrophy occurs in a voluntary muscle as the result of cessa- 
tion of function, whether this be due to ankylosis of the joint 



ATROPHY 



213 



oi a limb or to the removal of nervous influence. This atrophy- 
is frequently associated, as has been stated, with fatty degener- 
ation. Atrophy of the intestine occurs on the distal side, when 
an artificial opening joins the gut to the surface of the body, 




Fig. 73. — Mechanical congestion of the liver; " nutmeg " liver. 

A longitudinal section of a lobule is seen with a dilated central vein, which is 
•shown in the middle of the figure. Passing from this are the dilated hepatic capillaries, 
widely separating the groups of hepatic cells, those of the latter nearest to the central 
vein being atrophied from pressure. At the periphery of the lobule the hepatic cells 
have undergone fatty degeneration, as shown by the clear spaces in the figure. 

thus preventing the contents from passing into the lower part 
of the gut. All the coats of the intestine suffer equally. 
Atrophy of the heart cannot be ascribed to any particular 
cause. It is referred to as brown atrophy, owing to the 
increase of the pigment round the nucleus of the fiber. Brown 
atrophy is found in cachectic conditions and in advanced old 



2i 4 DEGENERATION AND REGENERATION OF CELLS, ETC. 

age, and is never found by itself, other organs of the body- 
being also degenerated. It is possible that it is due to a defi- 
cient amount of nutriment carried to the heart, though it is not 
associated necessarily with disease of the coronary arteries. 
Atrophy from pressure occurs in cases where the pressure is 
continuously applied for long periods. This is observed in 
the skin and in the liver cells from the pressure of the dis- 
tended capillaries in mechanical congestion (Fig. 73), and in 
the heart, liver, and kidney, from the pressure of contracting 
fibroid tissue. Intermittent pressure leads to hypertrophy of 
the epithelium of the skin. 

8. Necrosis. — Necrosis is a term applied to the condition 
in which death of the tissues occurs; gangrene is a term 
synonymous with necrosis. Necrobiosis has been used to 
denote the death of individual cells, but the term is unnecessary. 

Necrosis is either infective or non-infective, and may be 
classified as follows : 

( 1 ) Necrosis due to stoppage of the circulation. 

(2) Necrosis due mainly to disease of the central nervous 
system. 

(3) Necrosis produced by mechanical causes (heat, cold, 
electricity), by chemical poisons, or by pressure. 

(4) Infective necrosis, which may also be called inflam- 
matory or bacterial necrosis. 

1. Necrosis Due to Stoppage of the Circulation. — The cir- 
culation through the main artery of the limb, and of that sup- 
plying the toes and fingers, may be stopped by aneurysm or by 
thrombosis resulting from disease of the arterial wall, such as 
atheroma; pressure on the artery will produce the same 
result. Stoppage of the circulation by spasm of the artery 
has been supposed to occur in Raynaud's disease and in 
ergotism, but in the former of these conditions it has been 
shown that in some cases there is a definite arterial disease. 
In some cases of disease, in addition to the arterial changes 
there is disease of the walls of the veins, and subsequent 
thrombosis leading to complete stoppage of the circulation. 



NECROSIS 215 

This has been observed in cases of gangrene of the lower 
extremities. 

Death of the part, or gangrene, is observed in the toes 
and feet, and in the intestine following embolism of the 
superior mesenteric artery. In Raynaud's disease the toes, 
fingers, and ears may be affected, and in diabetic gangrene the 
lower extremities. Two varieties of the condition are described 
— dry and moist gangrene; they only differ according to the 
amount of fluid the part contains. Dry gangrene is observed 
usually as the result of embolism or thrombosis of the per- 
ipheral arteries. Ergotism also leads to dry gangrene as 
well as Raynaud's disease. Dry gangrene, produced by 
freezing, may be due to thrombosis. Dry gangrene tends to 
the formation of a slough which may include the extremity 
in the whole of its thickness, the separation of the necrosed 
and healthy parts being by a line of demarcation. In moist 
gangrene, venous thrombosis usually plays a part, thus leading 
to the accumulation of fluid in the necrosed area. It must 
be said, however, that the majority of cases of moist gangrene 
belong to the infective class. 

Coagulation Necrosis. — This is a form of necrosis which 
occurs as the result of stoppage of the circulation in certain 
organs, such as the kidney or spleen; it results in the death 
of the cell, which takes place by means of a process probably 
allied to rigor mortis. It is seen in its typical form in the 
formation of the white infarct of the spleen and kidney 
(Chapter XIII. ). In some cases, owing to the stoppage of the 
circulation through the main renal vessels, the whole kidney 
cortex may be in a state of coagulation necrosis. No recovery 
is possible from this condition. In this description coagu- 
lation necrosis is considered as a non-infective process. 
Frequently, however, the term is applied to certain changes 
produced by infective processes in tissues, such as the 
formation of fibrin in inflammatory areas and the subsequent 
death of the cells. This, however, is not the same process, 
and the term coagulation necrosis ought to be limited to the 
condition described, namely, to the death of the cell owing 
to the sudden stoppage of the circulation to the part. Fatty 



216 DEGENERATION AND REGENERATION OF CELLS, ETC. 

degeneration subsequently occurs in the areas affected by 
coagulation necrosis. 

2. Necrosis Due to Disease of the Nervous System (Chap- 
ter XIX). — Under this heading are described the formation of 
acute bed-sores and the occurrence of cystitis in acute disease 
and injury to the spinal cord, the so-called trophic changes 
which occur in the eye in paralysis of the fifth nerve, and the 
joint changes which occur in tabes dorsalis and some other 
chronic spinal affections. It has to be considered, however, 
how far these conditions are due to the disease of the nervous 
system, and how far to an infection readily occurring in a 
tissue in which the functional activity is diminished. Thus 
the cystitis of disease of the spinal cord is not due to the nerve 
disease directly, but is an infection of the bladder occurring 
in a damaged tissue. This is not a necrotic process. The 
same remarks apply to the eye changes occurring in paralysis 
of the fifth nerve. Acute bed-sores, on the other hand, 
appear to be directly related to the disease of the nervous 
system, and are not, at any rate in . the first instance, 
apparently infective in origin. The exciting cause is in some 
instances pressure on the part when lying in bed. 

Charcot's disease of the joints appears to be mainly a 
necrotic process, non-infective and dependent on the disease 
of the spinal cord. 

3. Necrosis Produced by Mechanical Causes (heat, cold, 
electricity) and by Chemical Poisons or Pressure. — Pressure 
necrosis is sometimes observed in the body from calculi and 
exostoses. This necrosis depends partly on pressure on the 
cells of a solid organ, or pressure on the organ driving out 
the blood or causing thrombosis. Pressure necrosis, therefore, 
comes really under the heading of necrosis due to a circulatory 
disturbance. 

Heat and cold, which may both produce necrosis, cause 
this result by killing the cells directly, heat leading to moist 
necrosis, cold leading as a rule to dry necrosis. The effect- 
of these agents in producing necrosis is, in the main, but little 
dependent on their effect on the local circulation. 

Chemical agents, such as mineral acids and caustic alkalies 



NECROSIS 



217 



and the corrosive salts of the metals, also act directly on the 
-cells of the part, destroying them. Ricin and abrin (p. 89) 
also produce necrosis of the cells by a direct action as do, also, 
many of the bacterial poisons. 

4. Infective Necrosis. — Many bacterial poisons are power- 
ful agents in producing the death of the cell or tissue. 
When injected under the skin of an animal they produce a 




Fig. 74. — Caseous tuberculosis of the lung. 

Part of the alveolar structure of the lung is seen, but the greater part of 
the figure is occupied by a tubercle, which contains four giant cells, and 
which shows in parts a collection of round cells, and in other parts an amor- 
phous caseous mass. 

result varying partly according to the dose administered and 
-partly according to their nature. If in a small dose or not 
highly toxic, they produce the phenomena of inflammation, 
in redness and swelling with edema. If in larger amount, 
or highly toxic, the ordinary phenomena of inflammation may 
be absent, and necrosis of the tissue follows. Necrosis of 
some of the cells of a part occurs as the result of any action 
of the bacteria, and a similar necrosis, which may be called 
inflammatory necrosis, occurs in local infections. Thus in a 



2 i8 DEGENERATION AND REGENERATION OF CELLS, ETC. 

diffuse infection (inflammation), which subsequently becomes 
localized, besides the phenomena of inflammation and the 
fatty degeneration of exuded leukocytes, there is a damage 
not only to the cells, but to the connective tissue of the 
part, which ends in necrosis, and this necrosis may be 
aided by thrombosis of the surrounding vessels. Although 




Fig. 75. — Bacterial necrosis. 

The figure was taken from a section of a nodule of bacterial necrosis - , 
(non-tuberculous) in the pharyngeal mucous membrane of the pig. 

A central clear area of necrosed cells is seen, with few nuclei, and these 
degenerating; surrounding this area is a peripheral zone of round cells 
(leukocytes). The nodule was sharply marked off from the surrounding 
healthy mucous membrane. 

Under a higher power the necrosed area was seen to consist mainly of 
amorphous matter, with a few cells and very numerous cocci, mostly 
arranged in chains. No other bacteria were present, including tubercle 
bacilli. 

the circulatory disturbance in an infective area may aid' 
necrosis, the chief agent in its causation is the action of the 
bacterial poisons. This necrosis may be seen in varying 
degrees in infective areas, from that observed in the forma- 
tion of a whitlow to the severe condition known as spreading 
gangrene. In this latter condition, from an inoculation, usually 
of an extremity, rapid infection of the limb ensues, with great: 




NECROSIS 



219 



brawny swelling and the destruction of all the tissues of the 
limb. Spreading gangrene is always of the infective variety. 
Another variety is spoken of as colliquative gangrene. This 
usually occurs in connective tissue or in loose tissue like the 
lung, and the name is given to denote the large amount of 
liquid containing fragments of necrosed tissue present in the 
gangrenous area. 




Fig. 76. — Bacterial necrosis. 

The figure shows the lower part of a Peyer's patch of the intestine of a 
guinea-pig, with the muscular and peritoneal coats attached. 

In the lower part of the patch is a nodule separated from the surround- 
ing normal lymphatic tissue, and composed of round cells undergoing 
degeneration (necrosis). In the nodule are two or three dark areas, which 
under a higher power are seen to be groups of bacilli. 

No tubercle bacilli were present, and the animal was not tuberculous. 

In the rest of the Peyer's patch were two or three similar necrotic areas. 



Other forms of infective necrosis may be described as 
caseous and bacterial necrosis. 

Caseation (Fig. 74) is observed as a result of the action of 
certain infective agents, such as those of tubercle and syphilis. 
It may also be observed, however, in non-infective infarcts 
(Chapter XIII.). It is a constant part of the changes in the 
lesions produced by syphilis and tubercle wherever they are 



2 jo DEGENERATION AND REGENERATION OF CELLS, ETC. 

formed. In the lesions of both diseases the main element is 
cellular, and is not supplied with blood vessels. No doubt the 
absence of blood vessels as well as, in a syphilitic lesion, the 
surrounding endarteritis, is partly the cause of the subsequent 
necrosis which commences in the central parts of the nodule, 
but probably a greater part is due to the action of the poisons 
of the infective agent on the cells of the nodule. The proc- 
ess is a chronic one, and has no relation to coagulation 
necrosis. • 

Bacterial necrosis (Figs. 75 and 76) is closely related to 
caseation. It is frequently observed in the liver, the spleen, 
and other organs of guinea-pigs and rabbits, as well as in the 
large herbivora. Whitish areas are observed, in which there 
is complete necrosis of the cells: numerous micro-organisms 
are present, which are not tubercle bacilli. The bacteria may 
be found in the vessels surrounding the necrosed area, but the 
process is evidently not due to stoppage of the circulation, but 
to a direct effect of the bacteria on the cells. 

9. Fibrosis. — This, when it affects certain organs, such as 
the liver and kidney, is called cirrhosis. When it affects 
the nervous system it is called sclerosis. The terms fibroid 
degeneration and fibroid substitution are also used, the former 
more particularly when the change affects organs such as 
the heart and kidney, and is primary; the latter when the 
fibrosis is secondary to a previous diseased condition of the 
part. Both these terms, are, however, unsuitable, and in 
discussing the pathological processes involved in fibrosis, the 
main condition to be considered is that the* process is essen- 
tially one of a new formation of fibrous tissue. It is not, 
therefore, strictly speaking, a degeneration, but is limited to 
certain changes which occur in fibrous tissue in disease, 
whether this exists as connective tissue or as a modified con- 
nective tissue, such as bone and cartilage. 

In the discussion of the various examples of fibrosis in 
disease, it will be evident (1) that an increase of fibrous 
tissue constituting fibrosis can only occur by changes occur- 
ring in the elements of previously existing connective tissue; 






FIBROSIS 221 

and (2) that this change is dependent on an injury whereby 
there is irritation of the connective tissue elements. 

The increase of fibrous tissue which is observed in fibrosis 
can only result, as has been said, from previously existing con- 
nective tissue (Fig. yy). In connective tissue, as is seen in 
the subcutaneous tissue and in the submucosa of mucous mem- 
branes, there are bundles of white connective tissue fibers. 




Fig. 77. — Chronic interstitial myositis. 

The early stage of this was shown in Fig. 6. 

The above figure shows the voluntary muscle fibers separated in parts— 
sometimes widely— by strands of connective tissue. The fibers themselves 
have undergone atrophy. 

and also elastic fibers, with the proper connective tissue cells, 
the tissue containing liquid, blood vessels, and lymphatics. 
Into this tissue, when it is affected by an injury or poison, 
the leukocytes of the blood immigrate. The connective tissue 
corpuscles undergo division, and when connective tissue is 
formed with the resulting fibrosis, the main elements in its 
formation are formoblasts — oval, pear-shaped, or spindle- 
shaped cells, with large nuclei; they elongate and not only 



222 DEGENERATION AND REGENERATION OF CELLS, ETC. 

form the cell elements of the new connective tissue, but also 
the white fibers. Elastic fibers are never formed in the 
new connective tissue of fibrosis. It has been discussed as 
to whether formoblasts are derived from the leukocytes or 
from the connective tissue corpuscles. There is no evidence 
as to their derivation from leukocytes, and, judging by 
analogy, it must be concluded that the main — perhaps the 
sole — source of origin of the formoblasts is a previously 
existing connective tissue corpuscle. The new connective 
tissue has new vessels formed in it by the apposition of cells 
in lines, a channel being subsequently formed. The new 
vessels are produced from the capillaries of the surrounding 
part. The white fibrous tissue of fibrosis frequently under- 
goes degeneration, especially when in large strands, the 
fibers becoming hyaline and staining but feebly with re- 
agents. The process of fibrosis above described is modified 
in some regions by the character of the connective tissue 
present, as, for example, in the central nervous system the 
connective tissue is represented by neuroglia, which is com- 
posed of very fine branching fibers with sparsely scattered 
cell elements. There is no reason to suppose that the process 
of fibrosis in the central nervous system is essentially different 
from that occurring elsewhere; the main part being taken by 
the glia cell elements present. 

The injury which results in fibrosis may be of different 
kinds. 

i. Fibrosis is part of the repair of wounds in which there 
is a solution of continuity and a destruction of some of the 
proper cell elements of the part. The amount of fibrous 
tissue formed in a wound when healing or healed depends, 
however, not solely on the degree of initial injury, but on the 
continued presence of an irritant in the wound, such as a 
foreign body, or, in infective wounds, bacteria and their 
products. 

2. The irritation of a non-infective foreign body in the - 
tissues leads to fibrosis. This may occur when a foreign 
body not containing bacteria is embedded in the subcutaneous 
tissues or other parts. It is also observed round necrosed 



FIBROSIS 223 

areas in the tissues, such, for example, as the fibrosis occurring 
round non-infective infarcts, where the area of dead tissue 
acts as a foreign body in producing irritation and fibrosis. 

3. In infective foci (inflammatory foci) fibrosis occurs 
(Figs. 78 and 79) ; it is observed round the focus when the ex- 
tension of the bacterial growth ceases, so that the infective 
focus may become completely surrounded by a fibrous capsule. 




Fig. 78. — Broncho-pneumonia (early stage) in Chronic 
Pulmonary Tuberculosis. 

The alveoli of the lung are seen packed with round cells, which are 
mainly leukocytes, but are in part derived from the alveolar epithelium. 
No fibrin was present. 

It also occurs in the infective focus itself, provided that com- 
plete destruction of the tissue does not occur, and is observed 
during the process of healing. The amount of fibrosis left by 
an infective focus after infection has ceased depends on the 
degree of destruction of tissue and the prolongation of the irri- 
tation. The greatest amount of fibrosis is observed in chronic 
infective foci, as, for example, in chronic tuberculosis. 

4. Fibrosis of the internal organs, either local or general, 



224 DEGENERATION AND REGENERATION OF CELLS, ETC. 

may result from the circulation in the body of toxic agents, 
both chemical and bacterial. Thus, in chronic alcoholism, 
extensive fibrosis of the liver is observed (cirrhosis of the 
liver, "gin-drinker's" liver), and the peripheral nerves may 
also show an interstitial fibrosis. 

With regard to the poisons of infective disease, but little 




Fig. 79. — Bronchiectasis, the result of infection. 

The figure shows a section of lung tissue under a low power. The 
alveolar tissue of the lung is seen, in many parts normal, but in other parts 
the alveolar wall is ruptured, producing an 'emphysematous condition. 

The bronchial tube is shown on the right side of the figure, with epithe- 
lium proliferated and muscle intact, but with a dilated lumen and with 
great thickening of the walls, which are composed almost solely of con- 
nective tissue. 

The spaces seen in the wall of the bronchus are partly blood vessels, and 
partly the remains of the alveolar tissue of the lung. 

(From a case of bronchiectasis following broncho-pneumonia in a child.) 

can definitely be stated. It appears, however, to be a fact 
that after infective diseases fibrosis of one or other organ 
may occur, more particularly of the liver, kidneys, and heart. 

Fibrosis of Special Parts. — Fibrosis of the heart muscle (Fig. 
80) is observed as the result of pericarditis, where the cause is 
obviously inflammatory, and occurs in hypertrophy of the left 



FIBROSIS 225 

ventricle, such as is observed in chronic renal disease. In the 
latter case the causation is not very obvious, but it may possibly 
be due to the circulation of a poison in the blood. Fibrosis 
of the lungs is observed usually after an infection such as that 
of tuberculosis, more rarely of pneumonia and of actinomy- 
cosis. It may also result from the inhalation of solid particles 
from the air. Fibrosis of the liver occurs in various forms. 




Fig. 80.— Fibroid heart. 

A section of the muscle substance of the heart is shown in which the 
muscle fibers are depicted, for the most part cut longitudinally. The fibers 
themselves show the nuclei, but are widely separated by strands of con- 
nective tissue, containing blood vessels, and in parts are atrophied by 
pressure of this connective tissue. 

In atrophic cirrhosis the irritant is alcohol, and the result is 
a multilobular cirrhosis (Fig. 81). In hypertrophic cirrhosis 
(Fig. 82) the irritant is unknown in some instances. In some 
cases it may be alcohol, in others the poison of an infective 
disease. In syphilitic cirrhosis the irritant is the syphilitic 
poison residing in the gummata. In cirrhosis secondary to 
chronic peritonitis the neighboring inflammation accounts for 
the condition. Fibrosis of the spleen is a rare condition unless 



226 DEGENERATION AND REGENERATION OF CELLS, ETC. 

it is associated with some form of infection, such as syphilis 
or malaria, with leukemia or with a degenerative change such 
as albuminoid disease. In some cases of prolonged mechanical 




Fig. 8i. — Multilobular cirrhosis of the liver under a low power. 

The normal lobular structure of the liver is lost, and the substance of 
the organ is broken up by thick strands of connective tissue into masses 
varying in size, each of which consists of several lobules of the liver. The 
liver cells are undergoing atrophy, pai'tly by pressure and partly by the 
cutting off of their blood supply. In the upper part, for example, there is a 
mass of liver cells which have almost completely degenerated, while in 
some parts, in the rest of the figure, the liver cells are practically normal in 
appearance. 

congestion of the spleen, the trabecule of the organ are 
thickened; the fibrosis that occurs is but slight in extent. 
Fibrosis of the kidneys is observed mainly in the chronic 
forms of renal disease; some of these are obviously the 



FIBROSIS 



227 



result of a previous inflammation; in other cases, such as that 
referred to as senile contracted kidney and the gouty kidney, 
the cause is not so obvious, although the condition is possibly 
due to the passage through the kidneys of irritant substances. 
In the nervous svstem, fibrosis is in some cases due to one or 




L.Fig. 82. — Unilobular or hypertrophic cirrhosis of the liver. 

The normal lobular structure of the liver is lost, and the substance of 
the organ is, as in multilobular cirrhosis, broken up into masses by thick 
strands of connective tissue, The masses, however, are smaller than in the 
multilobular variety, and may consist of only one lobule. There is advanced 
degeneration of the liver cells, and in the strands of connective tissue 
elongated tracts can be seen lined by cells. These are considered by some 
as small bile-ducts, and by others as the remains of liver cells. 

other form of infection, though the actual mode of produc- 
tion and the process of infection are at present but little under- 
stood. 



The Regeneration of Tissues. — This term refers to the 
process by which, after a portion of an organ has been 
destroyed, regeneration takes place, supplying the loss. The 
process, however, is comparatively limited. Any great 
destruction of a part is not regenerated, and the place of the 



228 DEGENERATION AND REGENERATION OF CELLS, ETC. 

part destroyed is occupied by fibrous tissue, by a cavity, or 
by an open wound. The individual tissues of the body vary 
considerably regarding their powers of regeneration, and it 
may be said generally that the more highly the tissue is 
specialized, the less power does it possess of regenerating. 
Thus with regard to nerve cells there is probably no regenera- 
tion; degeneration of a cell of the central nervous system 
means the loss of a cell. It is otherwise, however, with the 
peripheral nerves. With these nerves regeneration takes 
place in cases of solution of continuity, or of disease destroy- 
ing the axis cylinder, when the healthy part of the nerve is 
in apposition to the diseased or severed part. For the process 
of regeneration to occur, the new fibers formed must grow 
down in the track of the nerve, and probably in the primitive 
sheaths of the damaged nerve fibers. 

The question of regeneration of muscular tissue is of 
some interest, as the muscles, both voluntary and involuntary, 
undergo both in health and disease great variations in bulk 
and in activity. Thus hypertrophy occurs, and in hyper- 
trophy of both kinds of muscle not only is there an increase 
in bulk of each fiber, but an increase in the number of fibers. 
This is more particularly the case with the heart muscle 
and the involuntary muscle of hollow viscera. If, however, 
damage be done to a small part of a voluntary muscle or of 
the heart, regeneration of the muscle fiber in the part does 
not occur. The place of the damaged and dead fiber is taken 
by connective tissue and a scar results. 

The regeneration of connective tissue readily occurs from 
the surrounding healthy tissue, and by the same process which 
has been described in the repair of wounds. In connective 
tissue containing fat, the fat may also reappear, but the proc- 
ess is a slow one. With the modified connective tissues, 
such as cartilage and bone, regeneration takes place to a 
greater or less extent. Thus after destruction of a portion 
of cartilage the cells of the cartilage subdivide and form part 
of the new tissue, but this is for the most part composed of 
fibrous tissue, so that the regeneration is only partial and a 
scar results. A similar process takes place in the case of 



REGENERATION OF TISSUES 229 

bone. The new bone is formed by the cells of the periosteum, 
but not in so regular a manner as in the original bone, and 
in many cases the change is associated with great increase of 
fibrous tissue. 

Epithelial cells, more particularly those of the skin, are 
readily regenerated. Destruction of the cells over an area 
is followed by the reproduction of cells at the periphery of 
the destroyed area, which gradually spread as a thin layer 
over the exposed subcutaneous tissue. The cells themselves 
have a considerable degree of independent vitality, inasmuch 
as they may be removed from a portion of skin and grafted 
on to the surface of an open wound, thus forming the center 
for a new growth of epithelium. The epithelium of mucous 
membranes is also readily regenerated, the best example of 
which perhaps occurs in the healing of the ulcers of enteric 
fever. Subsequently to their healing but little evidence is 
obtained in the mucous membrane of previous ulceration. 
The epithelium of both the skin and mucous membranes is 
extravascular, and on this perhaps depends the great power 
of regeneration. 

The question of the regeneration of the cells of solid 
organs, such as the liver and kidney, and of the glands of 
mucous membranes, is not easily decided. With regard to 
the liver the cells are capable of subdivision, and it might 
be considered probable that in an irregular destruction of 
cells of the liver neighboring cells might divide and take 
the place of the destroyed cells. There is, however, but 
little direct evidence that this occurs. The cells of the liver 
are affected in cloudy swelling, from which recovery is possible 
without destruction of the cell. When the cell, however, un- 
dergoes fatty degeneration, some of the cells are destroyed, and 
regeneration may occur from the surrounding cells. Indeed, 
in prolonged illness from infective disease, it is probable that 
some of the cells of the liver undergo fatty degeneration, and 
yet complete recovery of bodily health may ensue. 

The regeneration of the cells of glands, tubular or acinous, 
and of the kidney tubules, must be considered as doubtful, 
unless one or more cells remain comparatively normal. If 



230 DEGENERATION AND REGENERATION OF CELLS, ETC. 

all the cells of an acinus or tubule are destroyed, it must 
be considered extremely doubtful whether regeneration can 
occur from the cells of the duct of the tubule or gland. 
Indeed it is frequently observed that in such cases the acinus 
or tubule forms a cyst, in which the cells show complete 
degeneration or are absent, their place being taken by 
fluid. 

Hypertrophy of muscular tissue has already been referred 
to (p. 228). There remains for consideration the so-called 
hypertrophy of organs. Hypertrophy of a part is not 
synonymous with enlargement, which may be due to many 
different conditions — inflammatory and otherwise. The term 
must be limited to the enlargement of an organ to compensate 
for the loss of tissue in another part of the organ. If one 
lobe of a lung is congenitally small, the other lobe is greatly 
enlarged so as to compensate for the diminished size of the 
smaller lobe. If one kidney is congenitally atrophied, the 
other kidney is much larger than normal. These examples o£ 
enlargement, however, occur during the process of intra-uterine 
and early extra-uterine development, and cannot be considered 
as in the same class as the question as to whether destruction 
of a portion of lung during life leads to a compensatory 
hypertrophy of another part of a lung, or whether destruc- 
tion of a portion of one kidney or of the whole of one kidney 
leads to hypertrophy of the other. It may be said with 
regard to the kidney that there. is no evidence that a true 
hypertrophy or an increase of the proper renal tissue occurs 
to compensate for the loss of substance by disease. In the 
case of a lung, when the air-breathing capacity of one part 
is diminished or destroyed, the rest of the lung may enlarge, 
and this is called compensatory emphysema. In this case also 
there is no evidence of the formation of new alveoli, but only 
of the dilatation of pre-existing alveoli and so of an increased 
air-containing capacity. 



CHAPTER VIII 

CHANGES IN THE CIRCULATION IN DISEASE 

Before proceeding to discuss in what manner the circula- 
tion may be affected in disease, it is necessary to discuss 
some of the facts regarding the circulation of the blood in 
health. 

The Heart and Vessels. — The central organ of the circula- 
tion is a force pump, which is sufficiently powerful for the 
complete circulation of the blood. Its activity depends on 
the integrity of the muscular substance and of the valves, as 
well as on the condition of the nervous system. The muscular 
substance has an independent rhythm of its own, which is 
well observed in the excised hearts of cold-blooded verte- 
brates. It is also seen in the excised mammalian heart, if 
means be taken to supply nutriment to the tissue. The con- 
traction of the heart muscle is, no doubt, propagated along 
the fibers by direct continuity, so that division of the fibers 
proves a great hindrance to the propagation of contraction. 
The condition of the healthy vessels is of great importance in 
the maintenance of the normal circulation. The arteries 
possess elasticity and contractility, dependent on the elastic 
tissue and the muscular layers. 

The circulation of the blood takes place in a closed system 
of tubes, the arteries contrasting with the veins in being over- 
full. On the elasticity of the arteries, as well as on the great 
resistance offered to the circulation in the capillaries, depends 
the fact that the intermittent flow of the blood from the 
heart is converted into a continuous flow in the small arteries, 
the capillaries, and the veins. The venous tension in the 

231 






232 CHANGES IN THE CIRCULATION IN DISEASE 

systemic circulation is much less than the arterial, and the flow 
of blood in the veins is somewhat more rapid as the larger 
vessels and heart are reached, owing to the suction action 
of the heart, as well as to the fact that the flow is from branched 
smaller vessels into large trunks. 

The pulmonary circulation differs from the systemic circula- 
tion in the fact that there is no great difference between the 
arterial and venous blood pressure. 

The Effect of the Nervous System on the Circulation is of 
the highest importance. The heart contains intrinsic ganglia, 
and is connected with the cardio-inhibitory center in the 
medulla by the vagus and sympathetic fibers. The rhythmic 
contraction of the heart is due partly to an independent mus- 
cular rhythm, as has already been mentioned, and partly to the 
presence of the intrinsic ganglia. In the mammalian heart, 
more than in the hearts of cold-blooded animals, this inherent 
property of rhythmic contraction is closely dependent on the 
supply of nutriment to the muscle fiber, and on the pressure of 
the blood in the cavities of the heart. The vagus and sym- 
pathetic fibers of the heart are the channels by which the organ 
is affected reflexly through the cardio-inhibitory center. 
Through the vagus, inhibitory impulses are transmitted to the 
heart, whereby the beat becomes less frequent, diminished in 
size, or ceases altogether. Through the sympathetic fibers, 
augmentor impulses are transmitted, whereby the heart beat 
is increased in force and in frequency. Section of the vagus 
nerves leads to augmentation; section of the sympathetic fibers 
does not, in all cases, lead to slowing of the heart, although 
such has been stated to be the case. 

The influence of the nervous system on the arteries is by 
means of the vaso-motor nerves connected with the vaso- 
motor center in the medulla; this center is mainly excited 
reflexly. The main vaso-motor nerves are the constrictors, 
stimulation of which leads to contraction of the artery, and 
section of which leads to dilatation. Active vaso-dilatation - 
may also occur. 

In health, the arteries of a part or organ vary in size, and 
so allow more or less blood to pass to the part. More blood 



NORMAL CIRCULATION 233 

passes when the organ is active than when it is in a resting 
-state, and this mechanism, which comes into action rerlexly 
through the vaso-motor center, plays, as is obvious, a great 
economic role in the circulation of the blood. The dilata- 
tion of the arteries of a small area produces no appreciable 
effect on the circulation of the blood or on the general arterial 
tension, but if a large area of arteries is affected, then there 
is a general lowering of blood pressure. This, for example, 
occurs when the arteries of the abdominal area supplied by 
the splanchnic nerves are dilated, leading to fullness of the 
abdominal veins. 

The pulmonary arteries have been shown to possess vaso- 
motor nerves, but their effect is much less than on the 
systemic arteries. Thus, similarly, with the arteries of the 
"brain; nervous fibers are found in the pia mater, but the 
circulation in the brain is not directly affected by innervation 
from the vaso-motor center, and the blood pressure follows 
that of the general systemic circulation. 

Circulation of the Blood in Disease. 

The circulation of the blood in disease is affected by — (1) 
The condition of the heart; (2) the condition of the blood 
vessels; (3) the condition of the central nervous system, as 
affecting the heart and vessels. 

The ways in which the circulation may be affected are 
manifold, and comprise: 

t. The effect of general disease, which may act either by 
affecting the supply of nutriment to the tissues under con- 
sideration, as. for example, by impoverishment of the blood 
( diminution of oxygen, increase of carbonic acid, diminution 
of proteids). or by the circulation of poisons which may have 
a specific effect on the heart itself, sometimes on the blood 
vessels, and frequently on the nerve centers connected with 
the vascular system. 

2. By local disease of the heart or vessels. 

A. Effect on the Circulation of Disease of the Heart. — This 



234 CHANGES IN THE CIRCULATION IN DISEASE 

will be discussed under the headings — i. The Effect of Diseases, 
of the Pericardium. 2. The Effect of Changes in the Muscular 
Substance, and the Effect of Disease of the Coronary Arteries. 
3. Disease of the Valves and the Effect of Malformations. 

I. Effect of Diseases of the Pericardium. — The pericardial 
sac is of great value in the normal action of the heart, as it 
allows the contractions of the organ to take place without em- 
barrassment by the surrounding organs. It is affected in many 
different ways by disease : by inflammation, which may cause a 
rapid effusion into the sac or subsequent adhesions ; by a slow 
and passive effusion, as in general dropsy; by new growths 
passing in from without; or by hemorrhage into the sac. Of 
these conditions, however, the most important from the present 
point of view are the occurrence of inflammatory effusion and 
the occurrence of general adhesions. The effect of inflamma- 
tion without these conditions is on the muscular substance, and 
will be discussed under that heading. 

Effect of Pericardial Effusion. — The effect on the circulation 
of the blood of fluid in the pericardial sac does not necessarily 
depend on the amount of liquid present. Large quantities 
of fluid may be present in the sac without producing any 
obvious effect on the circulation. This occurs in cases of 
passive effusion, where the liquid is slowly thrown out, and 
the sac accommodates itself to its increased contents. It is 
in active effusion, where the liquid is rapidly thrown out, 
that effects are observed. The main factor in producing an 
effect on the circulation is the degree of tension of the liquid 
in the pericardium. Normally, the sac shows a negative 
pressure of 3 to 5 mm. of mercury, and it is when this 
pressure becomes positive and is rapidly increased, that effects 
are observed. The main results are a small, compressible 
pulse, varying greatly in frequency, though usually above 
the normal; muffled cardiac sounds, with an increase of dis- 
tinctness of the second pulmonary sound ; a diminished arterial 
tension, and an increased venous tension, which is sometimes 
evidenced by cyanosis and turgescence of the veins of the upper 
part of the body. 



EFFECT OF PERICARDIAL EFFUSION 235 

There is experimental evidence to show that the effects of 
pericardial effusion on the circulation are due to the degree 
of tension of the fluid in the sac (Cohnheim). 

In testing the effect of pericardial effusion, the sac was 
filled with varying quantities of warm oil by a tube which 
was connected with a manometer. Not only is the tension 
in the pericardium thus measured, but, by injecting more and 
more oil, it can be increased. At the same time tracings 
were taken of the blood pressure in the femoral artery, the 
jugular vein, and in the pulmonary artery and veins. If 
the oil is slowly injected until the pericardial pressure rises 
to 30 or 40 mm., there is but little effect, but if the tension 
is increased to double this, two results are observed : in the 
first place, the arterial pressure falls 20 or 30 mm. of Hg, and 
the venous pressure rises 60 mm. of soda. This is in the 
systemic circulation, and the same results are observed if the 
pericardial pressure be even further increased. Thus, when it 
rises as high as 100 to 120 mm., the pressure in the femoral 
artery falls one half, the respiratory and systolic elevations 
and the blood pressure being diminished. The venous pres- 
sure rises still higher than before, up to 100 mm. of soda. 
The removal of the pericardial pressure causes a return to 
the normal condition. Still greater pressure in the pericardial 
sac causes a still greater increase of the venous pressure, while 
the arterial pressure diminishes until the systolic elevations are 
no longer observed in the curve, and the animal is pulseless. 
Recovery is still possible if the pericardial pressure be rapidly 
removed; otherwise death ensues. 

The pulmonary circulation does not behave in quite the same 
manner as the systemic. There is normally but little differ- 
ence between the pressure in the pulmonary artery and vein, 
contrasting strongly with the great difference of pressure in 
the aorta and f he large systemic veins near the heart. In the 
overfilled pericardium, the pulmonary arterial pressure falls, 
but the venous pressure also falls, unlike what occurs in the 
systemic veins. 

The pressure of the blood within the arteries depends on — 
(1) The resistance offered to its passage through the small 



236 CHANGES IN THE CIRCULATION IN DISEASE 

arteries and the capillary network; (2) on the power of the* 
left ventricle; and (3) on the amount of blood discharged at: 
each ventricular contraction. 

In the experiments under consideration, conditions (1) and. 
(2) are unchanged, so that the fall of blood pressure is not- 
dependent on any change in the peripheral resistance or in: 
the power of the left ventricle. The diminution of blood press- 
ure depends on the third factor, that is, on the diminution* 
in the amount of blood discharged at each ventricular contrac- 
tion. This diminished output is a sequence of the diminished' 
flow of blood into the heart during diastole. A rise of venous- 
pressure does not necessarily follow a fall of arterial, as, after 
section of the cervical cord, it does not rise, although there- 
is a great fall of arterial pressure. 

The cause of the rise of venous pressure in overfilled peri- 
cardium is the diminished flow of blood into the heart, whereby- 
the venous system becomes overfull. 

Venous Pulse in Pericardial Effusion. — According to some, . 
the venous stream into the auricle and ventricle is, normally, 
practically continuous, being but little affected by the auricular- 
systole. In overfilled pericardium, the venous blood may enter 
only during the diastole ; the contraction of the auricle as well" 
as the increased tension in the pericardium preventing its en- 
trance during the systole of the auricle. A pulsation in the* 
veins of the neck ensues. This pulsation is presystolic, preced- 
ing the ventricular systole, and it may be called the presystolic" 
venous pulse. The auricular systole, with the increased tension 
in the pericardium, momentarily prevents the entrance of blood" 
from the overfilled veins. The pulsation in these veins thus 
ensues during the contraction of the auricle. This venous; 
pulse may be compared with the systolic venous pulse, whicrr 
occurs in tricuspid regurgitation. This is produced by the- 
contraction of the right ventricle, imparting an impulse through 
the incompetent tricuspid valve into the dilated veins which 
enter the auricle. 

II. The Effect of Disease of the Heart Muscle on the Circu^ 
lation. — The continued action of the heart muscle in healths 



EFFECT OF DISEASE OF HEART MUSCLE 237 

depends on the integrity of the fibers and their continuity, 
on the integrity of the nerves and cardio-inhibitory center in 
the medulla, and on the supply of oxygenated blood through 
the coronary arteries. These arteries arise near the commence- 
ment of the aorta, and at each systole of the left ventricle blood 
enters them. 

1. Disorder of the Coronary Circulation. — The heart of 
cold-blooded animals will continue beating for some hours in 
the absence of a continuous supply of nourishment, but with 
the mammalian heart this does not occur, unless steps be taken 
to supply a continuous flow of nutrient fluid. If this is done, 
at a proper temperature the heart continues to beat for some 
time. If, in the rabbit, the coronary circulation be suddenly 
stopped, the heart ceases to beat; both sides simultaneously, 
or the right last. In the dog important results follow the lig- 
ature of one of the large branches. After about ninety seconds,, 
irregularity and infrequency of the cardiac beat is observed, 
followed by sudden stoppage in diastole. This is an important 
result, and may be explained by the fact that the contrac- 
tion of the layers of fibers of the heart is due in part 
to their continuity; a solution of continuity of the fibers 
prevents the proper propagation of the contraction. Thus, 
when fibers in the frog's heart are divided, perhaps only one 
impulse in three will pass over the gap made. The right and 
left coronary arteries supply different regions, and their anas- 
tomosing branches are but few in number. Ligature of a large 
branch would therefore seriously and suddenly interfere with 
the nutrition of a large area of muscle fibers, and thus the 
continuity of propagation of impulse would be interfered with. 
The ventricle beating imperfectly tends to dilate, from the 
accumulation of blood constantly pouring into it, and eventually 
the accumulation is sufficient to make the heart stop in 
diastole. 

The coronary arteries are frequently found diseased in 
middle and old age. Atheromatous patches are observed along 
their extent, but. more important than this, the orifices of 
one or both arteries may be stenosed, sometimes very consider- 
ablv. In some cases of sudden death, this stenosis of the 



238 CHANGES IN THE CIRCULATION IN DISEASE 

coronaries is the only lesion found to account for the fatal 
result, and it is evident that, if extreme, it is adequate to do so, 
inasmuch as the heart muscle receives much less blood than 
normal, and, if called upon to make a certain effort, as in un- 
wonted exercise, may fail to respond, and so cease to beat; 
in the same manner as when, in the dog, one of the large 
branches of the artery is ligatured. Disease and occlusion of 
the coronary arteries lead to changes in the heart muscle; 
more particularly to fatty degeneration of the muscle fiber 
(frequently patchy), and to the occurrence of fibroid patches, 
which are sometimes roughly triangular in shape, and may 
pass through the whole extent of one or other ventricle, more 
particularly the left. These fibroid patches, which are some- 
times met with in the hypertrophied left ventricle in renal dis- 
ease, have been ascribed to embolism of the coronary artery, 
leading to necrosis, and subsequent fibrosis. Disease of the 
coronary arteries may have some relation to the causation of 
angina pectoris, but the exact connection is at present impossible 
to define. 

2. Disease of the Heart Muscle itself. — The muscle fibers 
may be damaged in many different ways, which may be sum- 
marized as follows : 

(a) An intestinal inflammation may occur, in association 
with pericarditis, and lead subsequently to a diffuse fibrosis 
of the heart, whereby the muscle bundles are more or less 
widely separated. Similar diffuse fibrosis is met with in certain 
cases of hypertrophy of the left ventricle associated with 
chronic renal disease (Fig. 80). 

(b) Fibroid patches, as stated above, may occur, causing a 
solution of continuity in the muscle layers. 

(c) Degeneration of the muscular substance itself may 
occur. Cloudy swelling of the fiber occurs in acute infective 
disease, and may be followed by degeneration of the fiber. 
Fatty degeneration (Fig. 66) also follows certain intoxications, 
such as by alcohol, arsenic, and phosphorus. It occurs in pro- 
found anemias, and in malignant disease, and is associated 
with adherent pericardium. 

(d) Loss of muscle substance occurs in fatty infiltration of 



DISEASE OF T#E HEART MUSCLE 239 

the heart, which affects, at first, mainly the apex of both ven- 
tricles and the substance of the right ventricle. In this case, 
the increase of surface fat, as well as the spread of fatty tissue 
in between the muscle fibers, not only diminishes the actual 
amount of muscle, but causes a solution of continuity in the 
muscle fibers (Fig. 65). 

(e) Pigmentary degeneration of the fiber, or brown atrophy 
of the heart, is undoubtedly a sign of a damaged heart, but it 
is difficult to define exactly how much damage it means. The 
muscle fiber is atrophied as well as pigmented. The pigment 
visible is simply an increase of the normal pigment of the 
muscle fiber. 

The lesions which have been mentioned may affect the con- 
traction of the muscle fiber, and so the heart activity, in two 
different ways : - 

1. The muscle fiber itself may be greatly weakened, as in 
the case, more particularly, of cloudy swelling and of fatty 
degeneration, but also of the other conditions mentioned. 

2. The propagation of the impulse of contraction may be 
greatly hindered by the separation of fibers, as in the case of 
diffuse fibrosis and of fatty infiltration; or continuity may be 
actually destroyed, as in the case of fibroid patches. 

With all these conditions leading to diminished heart power, 
there is a tendency to accumulation of blood in the heart, and 
so to dilatation of the organ. 

Dilatation and Hypertrophy of the Heart. — As has pre- 
viously been stated, the regular beat of the heart depends upon 
more than one factor, namely, on the power of the heart 
muscle, on the degree of resistance in the peripheral arteries 
and the capillaries, and on the action of the nervous system on 
the heart itself. 

During health the mean arterial pressure remains fairly 
equable. In the early period of prolonged muscular exercise 
it is somewhat increased, owing, no doubt, to the sudden strain 
on the heart. The general tendency of muscular exercise is, 
however, to lessen blood pressure. On the other hand, it is said 
that sedentary occupations tend to increase the mean arterial 



24 o CHANGES IN THE CIRCULATION IN DISEASE 

pressure. Although the beat of the heart does vary somewhat 
in health, it is within very small limits. In disease, however,, 
the activity is greatly modified by : 

1. Structural alterations in the valves of the heart or the 
cardiac muscle. 

2. Structural alterations in the arteries. 

3. Increase of peripheral resistance in the arterioles. 

4. The influence of the nervous system on the heart 
itself. 

One of the results of these changes is dilatation of the 
cavities, with or without hypertrophy. Dilatation is associ- 
ated with hypertrophy, the latter being the natural mode of 
overcoming the former, or producing compensation, as it is 
called. Dilatation may affect all the cavities of the heart 
or it may be partial. In dilatation the cavities are over- 
filled, and this overfilling is an exaggeration in the ventricles 
of the normal condition, as these cavities probably never com- 
pletely empty themselves, even at the height of the ventricular 
systole. 

General dilatation of the heart results from three chief 
causes : 

1. One or other of the conditions weakening the muscular 
structure already discussed (p. 238). 

2. As the final result of a valvular lesion. This first leads 
to partial dilatation, but subsequently, owing to an increase of 
the lesion, the circulation of the blood through the heart may 
be so embarrassed that general dilatation occurs. 

3. As the result of an increased peripheral resistance, lasting 
for a considerable time (months or years). 

Whether hypertrophy accompanies dilatation or not depends 
on many factors. The heart muscle, like other muscles, has 
a reserve power, that is, it does not contract to its full strength. 
This is shown by the fact that stimulation of the augmentor 
fibers of the sympathetic nerves causes great increase in the 
strength of the contractions of a normal heart, as well as by 
the fact that a moderate degree of pressure exerted on the 
heart, as in the experiments with overfilled pericardium (p. 
234), leads to no alteration in the blood pressure; a similar 



D1LA TA T10N AND HYPERTROPHY 241 

result occurs when a moderate degree of obstruction is experi- 
mentally applied to the exit of blood from the heart by the aorta 
and pulmonary artery. 

In both these instances, the blood pressure does not vary 
because the heart contracts more forcibly. Within certain 
limits, the amount of blood in a cavity of the heart acts as a 
direct stimulus to its contraction. If, in disease, more blood 
enters the cavities of the heart, there is a greater effort on the 
part of the organ to expel its contents, and this effort continued 
for long periods (months or years) leads, under certain condi- 
tions, to hypertrophy of the muscle. 

The conditions under which increased action and hyper- 
trophy occur are ( 1 ) the degree of stress which is laid on the 
heart, and (2) the power of the heart muscle to undergo hyper- 
trophy. Thus, if the resistance to be overcome is too great, as in 
some instances of dilatation and in some cases of increase of 
peripheral resistance, hypertrophy may not occur, even in the 
absence of obvious disease of the muscle fiber. 

The main cause preventing hypertrophy is disease or mal- 
nutrition of the muscle fiber of the heart. 

The conditions in which hypertrophy of the heart occurs may 
be summarized as follows : 

1 . In some cases of prolonged overwork, as in young laborers 
and soldiers. In some prolonged cases of exophthalmic goiter 
there is hypertrophy of the heart, in which, no doubt, the main 
factor is the continued rapid action, with a healthy muscle 
substance. 

2. In valvular lesions hypertrophy results from the over- 
filling of one or more cavities. 

3. In adherent pericardium there is the same explanation. 

4. In renal disease hypertrophy of the left ventricle occurs 
as the result of an increase of peripheral resistance, due to 
fibrosis and contraction of the arterioles. In emphysema the 
right ventricle hypertrophies, owing to the increased resistance 
in the pulmonary arterioles. 

For hypertrophy to occur the muscle substance must be 
healthy, so that it is chiefly observed in young adults. 

The hypertrophy which is produced as a result of disease may 
16 



242 CHANGES IN THE CIRCULATION IN DISEASE 

be sufficient to overcome the embarrassment of the circulation ; 
in other words, the occurrence of hypertrophy may compensate 
for the lesion which has produced the defect in the circula- 
tion. But in many cases it is not sufficient. The muscle has 
hypertrophied to its full extent, which is not sufficient to 
carry on the circulation properly. When compensation is 
completely compensatory, the normal mean arterial pressure 
may be maintained, as in cases of slight valvular lesion, but 
when hypertrophy is not sufficient, the circulation is carried on 
with a diminished arterial pressure, so that there is a tendency 
to venous stagnation. 

In cases where hypertrophy is due to increased peri- 
pheral resistance, as in cases of chronic renal disease, 
the circulation is carried on at a heightened mean arterial 
pressure, which may, of itself, lead to serious results 
(P- 256). 

III. The Effect of Valvular Lesions on the Circulation. — 
The closure of the auriculo-ventricular orifices is for the 
purpose of preventing the blood passing back into the 
auricles when the ventricles contract, in order that it should 
go into the large arteries. Closure of the semilunar valves 
of aorta and pulmonary artery not only prevents regurgi- 
tation of blood into the ventricles, but is a great aid in 
maintaining the pressure in the arteries. These elastic 
tubes are overfull and are part of a closed system, which 
begins at the semilunar valves and ends at the auriculo- 
ventricular valves. 

In all valvular lesions part of the blood stream is diverted 
from its natural direction, so that there is a diminished normal 
stream; there is less blood sent into the aorta, and so there 
is a diminished arterial pressure. This is the case in the chronic 
lesions of the valves usually met with in disease. 

Stenosis of the Aortic and Pulmonary Orifices. — In both 
these cases there is obstruction to the exit of blood from the 
heart. Whether this occurs solely from disease of the valves, 
as in the case of the aorta, or from congenital malformation of 



VALVULAR LESIONS 243 

the pulmonary valves associated with some contraction of the 
artery itself, the obstruction tends to cause accumulation of 
blood in one or other ventricle, which thus has to contract more 
forcibly to expel its contents. 

It has been found experimentally that there are two periods 
of events, according to the degree of obstruction. Thus, 
if the obstruction is only moderate in degree, no change is 
observed in the femoral arterial pressure curve, or in the 
venous pressure curve taken from the jugular vein; that is, 
there is no alteration in either the arterial or venous pressure. 
If, however, the obstruction be very great, there is a steep 
and sudden descent of the arterial pressure. The absence of 
any change in blood pressure in moderate obstruction is due 
to the fact that the ventricle acts much more forcibly, there 
being an increased intraventricular pressure, and that this 
increased contraction is sufficient to drive the blood past the 
obstruction. With extreme stenosis this does not occur. In 
aortic obstruction, with diminished arterial pressure is asso- 
ciated an increased venous pressure. The cardiac beat is 
augmented, the pulse is infrequent and shows in a tracing a 
high rise with a flattened top. 

The main point shown by the experiment quoted is that, 
with a certain degree of obstruction produced by valvular dis- 
ease, the heart is capable of maintaining the circulation, hyper- 
trophy occurring to enable it to do this for months or even 
years. If, however, the obstruction is great, hypertrophy is in- 
sufficient and dilatation results. In the compensated cases, 
there is a tendency to dilatation, and it may be said that dilata- 
tion only becomes of pathological importance when the systolic 
contraction is unable to empty the cavity. 

Incompetence of the Aortic Orifice. — This, which is usually 
referred to as Aortic Regurgitation, occurs when the valves 
are not accurately apposed to each other, because the cusps 
are partly destroyed, distorted, or adherent. Various degrees 
occur, allowing a greater or less amount of the blood sent from 
the left ventricle to regurgitate after the ventricular systole. 



244 CHANGES IN THE CIRCULATION IN DISEASE 

the dilatation which occurs in well-marked cases of regurgita- 
tion is not explained by the small amount of blood which 
regurgitates immediately after the ventricular systole. In 
aortic incompetence the arterial system is no longer closed in 
the sense in which the word is used above (p. 242) . The lesion 
of the valves tends to make the left ventricle part of the arterial 
system, so that the tension of the blood in the arteries is con- 
tinuously being exerted on the walls of the ventricle during its 
diastole, and this continuous pressure is one factor in producing 
dilatation in such cases. There is thus never a negative pres- 
sure in the ventricle. 

Stenosis and Incompetence of the Mitral Orifice. — Disease of 
the mitral valve ends in producing rigidity and distortion of 
the valve, and shortening and adhesion of its chordae tendineae. 
The effect on the orifice is to produce constriction, resulting 
in obstruction and incompetence. The final effect on the orifice 
varies considerably. Thus, obstruction to the passage of the 
blood from the left auricle into the ventricle may be the 
chief defect present, as in the case of the so-called buttonhole 
mitral. In other cases, with some obstruction, the valve is 
permanently open by a narrow orifice, so that there is not 
only difficulty in the passage of the blood from the auricle to the 
ventricle, but during the ventricular systole part of the 
blood is diverted from the aortic stream back into the auricle. 
In still other cases, the valve, although stiff, is widely open, 
being held in this position by the shortened and adherent 
chordae. 

Incompetence of the valve may also be produced by 
dilatation of the left ventricle, as occurs in some cases of 
aortic valvular disease, in dilatation of the heart due to 
degeneration of the muscle substance, and in adherent peri- 
cardium. 

It is evident that the circulation would be embarrassed 
in different ways, according to the degree of stenosis or in- 
competence of the orifice. In extreme stenosis, without re- 
gurgitation, the left auricle becomes overfull, while the 
left ventricle is natural in size or even smaller than normal. 



VALVULAR LESIONS 245 

The increase of pressure in the left auricle obstructs the 
flow of blood in the pulmonary system, and the right 
ventricle tends to become overfull and so to dilate. Hyper- 
trophy of the left auricle may occur, although, when such 
hearts are examined after death, there is usually no evidence 
of hypertrophy. The chief means of overcoming embarrass- 
ment of the pulmonary circulation is hypertrophy of the 
right ventricle, and if the stenosis of the orifice be not 
extreme, this hypertrophy may be sufficient to carry on the 
pulmonary circulation efficiently for many years, although at 
an increased pressure. If, however, stenosis be extreme or 
the right ventricle be unable to hypertrophy sufficiently, 
either from pericardial adhesions, from fatty infiltration, or 
from degeneration of the muscular substance, dilatation of 
the whole right side of the heart occurs, resulting in tri- 
cuspid regurgitation and an embarrassment of the systemic 
venous circulation. In some of these cases, which have lasted 
many years, a thickening of the tricuspid valve, leading to 
stenosis of the orifice, is observed. Such an occurrence must 
be attributed to the long-continued increase of pressure on the 
right side of the heart. 

In cases where the incompetence of the mitral valve is greatly 
in excess of the stenosis, the results on the circulation are not 
the same as when stenosis is the only or predominant lesion 
present. There is, in such a condition, a free entry of blood 
from the pulmonary veins into the auricle and into the 
ventricle, but at the ventricular systole, a greater or less 
quantity of blood is sent back into the auricle through the 
incompetent valve. This tends to dilatation of the left 
auricle. This quantity of blood passes back again into the 
ventricle during diastole, as well as the further supply of 
blood from the pulmonary veins. The whole of the left 
side of the heart, therefore, obtains more blood than normal, 
and so tends to dilate, the dilatation being followed, in the 
case of the left ventricle, by well-marked hypertrophy. This 
hypertrophy is merely secondary to the increased pressure, 
due to the increased amount of blood in the left ventricle. 
It is a question how far it is beneficial in remedying the 



246 CHANGES IN THE CIRCULATION IN DISEASE 

defective circulation caused by the mitral incompetence. , If 
this is not great, it is evident that a more powerful con- 
traction of the ventricle will send a larger amount of blood 
into the aorta, as well as a larger amount back into the left 
auricle, but the more blood sent into the aorta, the greater 
is the relief to the pulmonary circulation, even though the valve 
lesion remains the same; so that, in slight degrees of incom- 
petence, the hypertrophy of the ventricle must be considered 
as beneficial. 

In great degrees of incompetence, however, the extra 
amount of blood sent by the hypertrophied ventricle into the 
auricle, as well as into the aorta, tends greatly to increase 
the embarrassment of the pulmonary circulation. in 
mitral incompetence, as will now be seen, for the hyper- 
trophy of the left ventricle to be beneficial in carrying on 
the circulation, there must be, in addition, hypertrophy of the 
right ventricle. The regurgitation of blood into the auricle 
at each ventricular systole tends to embarrass the pulmonary 
circulation. This embarrassment, accompanied as it is by 
an increase of pressure, throws increased work on the right 
ventricle at its systole, and its hypertrophy tends to relieve 
the embarrassment, even at the expense of increase in the 
pressure in the pulmonary area. 

It is now readily seen how hypertrophy of the right ven- 
tricle, associated with hypertrophy of the left, may compen- 
sate for the hindrance to the circulation caused by incompetence 
of the mitral valve. Thus, although the hypertrophied left 
ventricle tends to drive more blood into the aorta, as well 
as back into the left auricle, the hypertrophied right ven- 
tricle, acting more vigorously and increasing the pressure 
in the pulmonary system, contracting at the same time as 
the left ventricle, tends to diminish the quantity of blood 
sent into the left auricle by the left ventricle, SO' that this 
increase of pulmonary pressure leads to an increased quantity 
of blood being sent into the aorta. It is true that however 
much the right ventricle may hypertrophy, the pressure in 
the pulmonary area cannot even approximate that in the 
aorta, but the increase of pressure in the pulmonary area 



VALVULAR LESIONS 247 

with the hypertrophy of the left ventricle may be sufficient 
to carry on the circulation, with but few signs of embarrass- 
ment. 

In conditions where there is great mitral incompetence, 
and great dilatation and hypertrophy of the left ventricle, 
complete compensation is not possible, inasmuch as the 
increase of pulmonary pressure produced by the contraction 
of the hypertrophied right ventricle is insufficient to diminish 
appreciably the large quantity of blood sent back into the 
left auricle by the hypertrophied left ventricle. The continued 
dilatation of the left ventricle, in such cases, leads to further 
embarrassment of the circulation through the heart. 

Hypertrophy of the right ventricle necessarily occurs in 
cases of compensation in mitral incompetence. When com- 
pensation fails or is incomplete, owing to the great regurgita- 
tion of blood, or to the inability of the right ventricle to hyper- 
trophy, tricuspid incompetence ensues, and so a great embar- 
rassment of the general systemic venous circulation. 

Associated Valvular Lesions. — Lesions of the aortic valve 
or mitral valve may exist alone, but in some cases they are 
associated. The three main conditions to be discussed are : 

1. Where there are well-marked lesions of both valves. 

2. Where there is a slight lesion of one valve, and a well- 
marked one of the other, either aortic or mitral. 

3. Where the mitral valve is affected secondarily to well- 
marked aortic valvular disease. 

1 and 2. In the condition where both sets of valves show 
well-marked lesions, the embarrassment of the circulation 
through the heart is extreme, whether the aortic valve show 
mainly obstruction or incompetence, or the mitral valve show 
mainly stenosis or incompetence. Thus, the great hypertrophy 
produced by aortic obstruction leads if mitral regurgitation 
be present as well, to very great embarrassment of the 
pulmonary circulation, an embarrassment which cannot be 
overcome by any hypertrophy the right ventricle is capable 
of undergoing. The same remarks apply to the association 
of aortic regurgitation with mitral regurgitation. The 



248 CHANGES IN THE CIRCULATION IN DISEASE 

association of stenosis of the mitral valve with disease of the 
aortic valves is not uncommon. In this condition, although 
the left ventricle gets less blood from the left auricle, it is 
yet overfull, owing either to the obstruction or to the regurgi- 
tation of blood at the aortic orifice. It is evident, however, 
that if the disease be not excessive, great hypertrophy of the 
left ventricle would not lead at its systole to any increase 
of pulmonary pressure, and it might be great enough to drive 
a sufriciency of blood into the aorta, while the hypertrophy 
of the right ventricle might be sufficient to overcome a 
moderate obstruction at the mitral orifice. With a certain 
degree of mitral stenosis, therefore, associated with a slight 
degree of aortic valvular disease, the circulation of the blood 
may be maintained sufficiently for the needs of the economy. 
If the aortic valvular disease is, however, well marked, great 
dilatation of the left ventricle ensues and life is impossible, 
owing to the left ventricle being incapable of emptying 
itself. 

3. In cases of aortic valvular disease, sometimes when 
when there is obstruction, but more often when there is regurgi- 
tation, mitral regurgitation occurs without disease of the valve, 
owing to the dilatation of the left ventricle, and this second- 
ary mitral incompetence may lead to the results of embarrass- 
ment of the pulmonary circulation previously described. This 
functional dilatation of the mitral valve results from dilatation 
of the ventricle, which is caused either by a great degree of 
aortic valvular disease — so great that the hypertrophy is unable 
to compensate for it; by extra strain put on the heart, as 
in the following of a laborious occupation ; by weakness of the 
muscular wall, due either to fatty infiltration or degeneration, 
or by pericardial adhesions. 

B. Changes in Cardiac Force and Rate in Disease. — The 
cardiac rate in health varies within somewhat wide limits, 
but the variation is, as a rule, only momentary. It is called 
out by some special need of the organism. Age, sex, 
exercise, food, and sleep affect the rate. In the female the 
rate is somewhat greater than in the male. In infancy and 



CARDIAC RATE AND FORCE 



249 



.'he Average Rate 


per Minute is 


I50 




140 to 


130 


I30 " 


115 


115 " 


100 


IOO " 


90 


QO " 


85 


85 " 


80 


80 " 


70 


70 " 


60 


75 " 


65 



childhood the rate is more frequent than in adult life and old 
age,, as is shown in the following table (Kirke's Physiology) . 



Before birth 

Just after birth 

During the first year . 

During the second year 

During the third year 

About the seventh year 

About the fourteenth year 

In adult age 

In old age 

In decrepitude 



Exercise increases, for a time, the cardiac rate as well as 
the force of the contraction of the heart. A heavy meal 
also increases the rate of the beat; while, in sleep, the rate 
is diminished. Section of both vagi increases the cardiac 
rate, the inhibitory influence, reflected from the cardio-inhibi- 
tory center along the vagus, being thus removed. Stimula- 
tion of the peripheral end of the cut vagus at first diminishes 
the size of the beat, and, if the stimulus be great, stops the 
heart in diastole. Stimulation of the sympathetic fibers 
causes not only an increase in the cardiac rate, but also an 
increased force in contraction. The fibers conveying this 
stimulus are called augmentor fibers. The rate may also be 
affected reflexly. Peripheral irritation of a sensory nerve, 
or of a serous membrane, acts reflexly and slows the 
heart. 

In disease, the cardiac rate and force are, in many instances, 
affected by way of the nervous system, but other factors occur 
which also have a profound influence. These are abnormal 
conditions of the heart muscle and of the valves of the heart, 
and changes in the peripheral resistance. 

In health t!ie force of the cardiac beat shows variations 
only as far as the reserve muscular power of the heart will 
allow. Some of these variations are dependent on altera- 
tions in the peripheral resistance, but variations due to this 
cause are only momentary. Any prolonged increase or 






2 5 o CHANGES IN THE CIRCULATION IN DISEASE 

diminution of the peripheral resistance is an abnormal, and. 
so a diseased, condition. 
The heart rate is slowed : 

1. By the action of drugs, such as digitalis, muscarin, and 
others. 

2. In hypertrophy of the heart, more particularly follow- 
ing aortic valvular disease; and in increase of the peripheral 
resistance. 

3. In many cases of weakness of the muscular wall, as, for 
example, in fatty degeneration. 

4. As a result of disease of the brain, either of the meninges 
or of the cerebral substance. 

5. In certain unexplained, mainly toxic, but possibly func- 
tional, conditions, referred to as bradycardia. Examples of 
this occur in the convalescence of acute fevers, such as typhoid 
fever, in jaundice, and myxedema. 

The cardiac rate is increased : 

1. By the action of certain drugs, such as digitalis in large 
doses, atropin, and others. 

2. In cases of cardiac disease, in which, owing to disease 
of the valves (uncompensated), there is a hindrance to the 
normal passage of the blood from the heart. 

3. In cardiac failure, whether due to want of compensa- 
tion of a valvular lesion, to disease of the muscle of the heart, 
to an increased peripheral resistance, or to toxemia, such as 
that occurring in pyrexia and in exophthalmic goiter. 

4. By an effect on the central nervous system, the cardio- 
inhibitory center being affected by functional or organic disease 
of the other parts of the brain, or reflexly from the organs 
of the body. 

The cardiac rate becomes irregular : 

1. In valvular lesions, such as those of the mitral valve in 
which the wave of contraction is interfered with. 

2. In weakness or disease of the muscular wall. 

3. As the result of a profound toxemia. 

4. As the direct effect of disease of the brain. 

An explanation of the changes of the cardiac rate in 
disease is, as is evident, by no means simple. Thus, slowing 



CARDIAC RATE 251 

of the heart occurs in some instances in association with an 
altered condition of the muscular substance. It is observed 
in hypertrophy of the left ventricle following aortic obstruc- 
tion, and, in this case, a slow action is associated with the 
increased strength necessary to drive the blood from the left 
ventricle into the aorta. But a slow rate may also be as- 
sociated with fatty degeneration of the muscular tissue, and 
the explanation is, in this case, that it is due to the fact that 
the muscle is weak and takes a long time to expel the blood 
from the heart. Slowing due to the action of drugs may 
be caused by an action either on the muscular substance or 
on the intrinsic ganglia of the heart. The chief examples of 
slowing of the rate occur as a result of direct or indirect ex- 
citation of the vagus center. Owing to excitation of this 
center, slowing occurs in asphyxial conditions, carbonic acid 
being the irritant. Reflex slowing is the explanation of the 
diminished cardiac rate in cerebral affections. In those in- 
stances of bradycardia occurring after infective disease, the 
explanation appears to be twofold, the diminished rate being 
due to an effect of the poison either on the muscular substance 
or on the vagus center itself. The latter explanation is more 
probably the correct one. 

Acceleration of the cardiac beat also does not admit of a 
simple explanation. It may be due to an affection of the 
nerve center, to an altered condition of the muscle of the 
heart, or to a hindrance to the normal circulation of the 
blood through the heart, and all these conditions may end 
in so-called cardiac failure, in which there is a gradually 
increased frequence of the cardiac beat, with a fall of blood 
pressure. Increase of the cardiac rate, due to an affection 
of the nerve center, is observed in pyrexia, in which it must 
be ascribed to a paralysis of the vagus center. It is some- 
times said that this paralysis is caused by the circulation of 
the hot blood. This explanation, however, does not appear 
to be adequate. The increase of cardiac rate varies con- 
siderably in pyrexia (p. 39), not only in different individuals, 
but in different febrile diseases, and although, in so-called acute 



252 CHANGES IN THE CIRCULATION IN DISEASE 

fevers, the average rate of increase is about ten beats per minute 
for i° F. rise of temperature, yet this proportion of increase 
does not hold good, even for many cases of high or even 
moderate pyrexia. Moreover, in some of these conditions the 
increased cardiac rate not only persists, but may actually first 
manifest itself, after the pyrexia has ceased. It appears more 
rational to ascribe the increased cardiac rate to an effect of 
the poison of the infective disease in paralyzing the vagus 
center. Similar paralysis of the vagus center is observed in 
the later stages of some cerebral affections, meningitis or 
cerebral tumor. 

In functional conditions of the central nervous system, 
grouped together as neurasthenia, an accelerated cardiac rate 
is observed, as well as in exophthalmic goiter, and, in both 
these cases, acceleration may be ascribed to paralysis of the 
vagus center. 

Acceleration may be due to weakness of the muscular sub- 
stance, as in fatty degeneration, in fatty infiltration, and in 
infective disease, when the muscle fiber undergoes degenera- 
tion. In the first two cases, the acceleration is due to the in- 
effectual efforts of the heart to empty itself, and is, no doubt, 
increased by a reflex effect on the cardiac center in the medulla. 
In the case of an infective disease, the acceleration is due to 
the effect on the muscle fiber, as well as to the direct effect 
on the vagus center already considered. 

In valvular disease acceleration is noted when there is 
want of compensation, and more particularly in cases of 
mitral disease. The prime cause of acceleration is the 
disturbance of the circulation of blood through the heart, 
and, no doubt, in mitral disease, to the disturbance of the 
circulation in the left auricle, and subsequently in the right 
heart. Reflex stimulation, starting from the auricle, affects 
the heart center and increases the cardiac rate, which must 
be considered as, in part, an attempt of the heart to* force 
on the blood by rapid contractions. 

Irregularity of the cardiac beat, either in force or rhythm, 
arises either from conditions in the center in the medulla, 



CARDIAC RATE 253 

or in the heart itself. The irregularity that is so commonly 
associated with disease of the mitral valve, either stenosis 
or incompetence, is a sign of want of compensation of the 
valvular lesion. 

The regular rhythm of the heart is dependent partly on the 
contractions initiated in the auricles and passed on to the ven- 
tricles, and the degree of contraction of a cavity is dependent 
on the amount of work to be done, i. e., the tension of the 
blood in the cavity. In mitral disease, the work of the left 
auricle is increased by its containing too much blood and by 
the obstruction at the mitral orifice. When compensation is 
adequate, the contraction of the left auricle, aided by the in- 
creased force of the hypertrophied right ventricle, may be 
sufficient to initiate regular contractions of the heart. When 
compensation is inadequate, the contraction may at one time 
be more powerful than at another, and so alterations in the 
force of contraction of the heart result. Irregularity in rhythm 
may be explained in the same way, some of the initiating con- 
tractions of the auricle not being sufficiently powerful to cause 
a general contraction of the ventricles. 

In many instances where compensation is adequate during 
quietude of body, irregularity is induced by muscular exer- 
tion. In normal conditions, more stress being thrown on 
the heart by exertion, it would beat more rapidly and power- 
fully, and the blood would pass more quickly through it. 
The embarrassment of the circulation of the blood in the 
left auricle in mitral disease would be increased by the 
greater flow of blood to the heart, and by the attempts to 
beat more rapidly. That this interference with the initiat- 
ing: impulse of the auricle is one of the chief causes of the 
irregularity observed in disease of the mitral valve, is shown 
by the fact that irregularity of the heart is not nearly so 
common a symptom in aortic valvular disease, and when it 
does occur, it is due to another cause, namely, a weak action 
of the muscular substance, associated with degeneration of 
the muscular fibers. 

Weakness or disease of the muscular wall may be the cause 
of irregularity in the action of the heart, as in fatty degenera- 



254 CHANGES IN THE CIRCULATION IN DISEASE 

tion, fatty infiltration, and the degeneration of the muscular 
substance observed in infective disease The main cause of the 
irregularity in these instances is the weak contraction of the 
muscular fibers. Their power is inadequate with every con- 
traction to empty the heart; that is, the work to be done is 
more than the muscle can perform. This would necessarily 
lead to irregularity in the contraction of a normal regularly 
contracting muscle. The heart, having lost its reserve power 
of contractility, might, for a certain number of beats in the 
minute, contract sufficiently forcibly, but after this effort it 
becomes exhausted and drops one or two beats. Irregularity 
is therefore observed in cases of cardiac failure. 

The regularity of the heart may also be affected through 
the cardio-inhibitory center in the medulla. An irregular beat 
is not infrequently observed in affections of the brain, either 
tumor or meningitis, and this is to be explained by a reflex 
effect on the medullary center or by a direct effect, owing to the 
increased intracranial pressure. It also results from the direct 
action of poisons on the center, as in excessive tobacco-smoking. 
Irregularity may also be caused by an effect on the center 
through the sensory nerves of the periphery, as is observed 
in cases of severe pain or vomiting, and, more particularly, 
when there is a slight lesion of the mitral valve, or some 
degeneration of the muscle substance. Whether the cardio- 
inhibitory center can initiate impulses to the heart or not 
is not decided, but it is clear that, in certain conditions of the 
center itself, it may, as a result of reflex stimulation, send to 
the heart, during a certain short period of time, impulses vary- 
ing in intensity, either inhibitory, along the vagus nerve, or 
augmentor, along the sympathetic fibers. This would lead 
to irregularity both in force and rhythm of the cardiac beat. 
It is more likely to occur in a damaged center, and this is 
observed, not infrequently, in moribund conditions, in which 
the vagus center, as well as other parts of the nervous system, 
is affected. 



• 



C. Effect of Arterial Disease on the Circulation of the Blood. 
— The main factors in maintaining the normal circulation of 



EFFECT OF ARTERIAL DISEASE 255 

the blood have already been discussed, as well as the manner 
in which the circulation may be affected by the altered con- 
ditions of the heart in disease. Disease of the arteries may 
also affect the circulation, and in two ways — local disease 
affects the circulation of a particular part or organ; while 
general disease of the arteries has an effect on the main 
arterial blood-pressure, and so on the activity of the heart. 

1. Effects of Local Arterial Disease. — The local diseases 
here under consideration are: Atheroma (Fig. 83), which 
may be either local or general; syphilitic arteritis (Fig. 84) ; 
tuberculous arteritis (Fig. 47) : and the periarteritis of the small 
vessels of the brain, which leads to the formation of miliary 
aneurysms. Disease leads, in the case of atheroma, to a loss of 
contractility and elasticity of the arterial wall, and to an en- 
largement of the lumen of the vessel. In the case of syphilitic 
arteritis, the disease is more local and leads to narrowing of the 
vessel. Normally the supply of blood to a tissue varies accord- 
ing to its activity, and the amount is regulated by the action of 
the vaso-motor nerves. During activity the vessels are dilated, 
and more blood passes to the part. During rest this physio- 
logical congestion disappears. If the artery has lost its elas- 
ticity and contractility, this physiological effect is not observed 
during activity, and an insufficient supply of blood thus results, 
when most needed by the tissues; disorders of nutrition there- 
fore occur (Chapter XVIII.). 

The arterial area affected by the disease is of importance. 
Thus, when atheroma affects the peripheral arteries, great 
defects of nutrition may occur in the muscles; but when it 
affects the vessels at the base of the brain only, no nutrition 
defects may be observed if the heart is normal and the mean 
arterial blood-pressure is maintained, inasmuch as the circula- 
tion of the blood through the brain is dependent on the general 
arterial blood-pressure. 

In syphilitic arteritis of the arteries of the base of the 
brain, however, the circulation is affected, inasmuch as the 
lumen of the vessels is diminished, so that, the general circu- 
lation not being affected, there is a deficient supply of the 
blood to some parts of the brain leading to defects in nutrition. 



256 



CHANGES IN THE CIRCULATION IN DISEASE 



Local disease of the arteries leads to thrombosis (Chapter 
XIII.) and to aneurysm. An aneurysm of the peripheral 
arteries has no effect on the general circulation ; the circulatory 
defect is local, and dependent on the amount of blood which is 
allowed to pass through the aneurysm. With aneurysm of 
the aorta, the local dilatation of the vessel no doubt hinders, 
to some extent, the proper circulation of the blood, inasmuch 
as the vessel has lost its elasticity and contractility; but there 
is no increased resistance to< the circulation of the blood, and 
so there is no hypertrophy of the left ventricle. 

2. Effect of Widespread Disease of the Arteries. — The arteries 
throughout the body may be affected by a condition described 

as angio-sclerosis (arterioscle- 
rosis) (Thoma). This includes 
two different conditions : athe- 
roma and arterio - capillary 
fibrosis (Figs. 83, 85, and 86). 
Both these changes may be 
observed in the same individ- 
ual. The effect of widespread 
disease depends on the nature 
of the disease and on the part 
affected. Thus, atheroma, which 
may affect in some instances 
the peripheral arteries of the 
body throughout the greater 
part of their extent, leads to 
dilatation and elongation of 

are practically normal, but the internal f i V ~ QQ ~1 ^rU'irh ciihcpmiAnrhr 

coat in one part is greatly thickened by m e VeSSd, WniCU SUDSeqUentiy 

the formation of almost hyaline connect- U~ rnrnpQ rrirt iiniic qc w^11 oc tr> 

ive tissue. In the part of this connective DeCOmeS tOrtUOUS, aS Well aS tO 

t splce e s Iiear the elastic laminae are clear a loss of contractility and elas- 
ticity of the arterial wall. The 
arterioles, that is, the arteries just before they break up into 
capillaries, are usually not affected by the disease. On the 
other hand, it is the arterioles and smaller arteries which are' 
affected in arterio-capillary fibrosis. Arterio-capillary fibrosis 
leads to diminution of the caliber of the artery and to a loss 
of elasticity; but, in the early stages, there may be hyper- 




Fig. 83.— Atheroma. 

Transverse section of a small artery, 
in which the external and middle coats 



EFFECT OF ARTERIAL DISEASE 



2 57 



trophy of the muscular coat and so an increased contractility. 
In any case, the condition leads to a great increase in the 
peripheral resistance to the circulation, so that it is difficult 
for the blood to pass from the arterioles into the capil- 
laries. In widespread atheroma of the arteries, without 
disease of the arterioles, there is no increase of the periph- 
eral resistance, and there is no difficulty in the passage of 




Fig. 84.— Syphilitic arteritis. 

A transverse section of an artery is shown, in which the lumen is greatly- 
narrowed and distorted. All the" coats of the artery are thickened, the 
most marked thickening being in the internal and external coats. 

(From a section near a local syphilitic lesion.) 



the blood from the arteries into the capillaries and veins. 
The loss of elasticity and contractility leads to a diminished 
mean arterial blood pressure, so that there is a tendency to 
stagnation of the blood in the veins, or rather to a diminished 
venous blood pressure. In arterio-capillary fibrosis, on the 
other hand, the mean arterial blood pressure must be increased 
for the circulation to be maintained. 

The maintenance of the arterial blood pressure depends, 



258 CHANGES IN THE CIRCULATION IN DISEASE 

not only on the condition of the arteries, but also on the 
condition of the heart; so that the cardiac force and cardiac 
capabilities must be taken into account in considering the 
observed effects of peripheral disease of the arteries on the 
circulation. Arterio-capillary fibrosis is associated with an 
increase of the mean arterial blood pressure, more particularly 
in cases of chronic renal disease. Owing to the increased 




Fig. 85. — Arterio-capillary fibrosis. 

A transverse section of two small arteries of the kidney is shown, with 
some of the renal substance, which was extensively fibroid. 

The vessels show some thickening of all the coats, but mainly a fibroid 
thickening of the intima, diminishing the lumen of the vessel. 



resistance in the arterioles, the heart has to act more forcibly 
in driving the blood into the capillaries. This leads — in the 
course of months and years — to hypertrophy of the left 
ventricle, the right being unaffected. This hypertrophy is 
a necessity for the maintenance of the circulation in this 
condition, and is indeed compensatory to the disease of the 
arterioles. Atheroma of the peripheral arteries may be 
associated with this condition; but, provided that the heart 



EFFECT OF ARTERIAL DISEASE 



259 



is hypertrophied, and still capable of powerful contraction, 
the mean arterial blood pressure is still high. The heart 
muscle, however, from one or other of the causes previously 
discussed (p. 238), may not be capable of powerfully contract- 
ing or of undergoing hypertrophy. In this case, then, there 
is a weakly acting heart, as well as an increased peripheral 
resistance, and the left ventricle dilates. Conditions varying 




Fig. 86. — Arterio-capillary fibrosis. 

The figure shows a transverse section of several small renal arteries. 
The lumen is contracted irregularly in the different vessels, due to an 
irregular thickening of the coats. In some the intima is chiefly affected, 
while in others the muscular coat is the chief one thickened. (F. W. Mott.) 



between the two extreme cases described are frequently 
observed. A weakly acting heart, when made to contract more 
powerfully, as by the administration of strychnin or digitalis, 
is observed to increase the mean arterial blood pressure; so 
that, in an individual with chronic renal disease and a low 
arterial blood pressure, this may become obviously increased 
by the administration of these drugs. Again, the high 
arterial blood pressure in chronic renal disease may be in- 
creased by certain conditions, such as constipation or bronchitis. 



260 



CHANGES IN THE CIRCULATION IN DISEASE 



or may be diminished by purgation, and by the administra- 
tion of certain drugs, such as amyl nitrite and erythral 
nitrate. The action of these drugs in reducing the arterial 
blood pressure has been ascribed to an effect on the arterioles, 
which are thereby dilated, and from this it may be concluded 
that a portion, at any rate, of the increased peripheral resist- 
ance is due to a muscular contraction of the arterioles. But 
it is possible also that part of the effect is due to an action 
on the heart, whereby its activity is diminished. 



Measurements of the Blood Pressure in Man. — The increase 
or diminution of the arterial blood pressure is commonly 
gauged by means of the finger ; and the " tension of the 
pulse," as it is said, estimated by the degree 
of pressure which is required to obliterate it. 
This, however, is not an accurate method, 
and, practically, determines only the extremes 
of arterial blood pressure. A more accurate 
means of determining the arterial blood 
pressure is by a sphygmometer (Hill & Bar- 
nard). This consists of a vertical glass tube, 
expanded above into a small bulb, closed by 
a glass cap, as in the figure (Fig. 87). A 
tube is attached below to a small india- 
rubber bag, which is filled with colored 
fluid. The tube is graduated from zero to 
200°, representing millimeters of mercury. 
To take an observation the tap is opened, 
the clamp attached to the wrist, and the bag placed over the 
artery. Gentle pressure on the bag brings the liquid up to 
zero, when the tap is closed. The bag is still further pressed 
down by means of the clamp on to the artery, causing the 
red liquid to rise in the tube, and the liquid exhibits pulsa- 
tions corresponding to those of the artery. The maximum 
pulsation is the reading of the mean arterial pressure. In 
healthy young adults the normal blood pressure in the radial 
artery is from no to 120 mm. Hg., and is constant. When 
lying down, the pressure is slightly less. During muscular 



Fig. 87.— Hill & 
Barnard's sphyg- 
mometer. 

(For description, see 
the text.) 



CAUSES OF ARTERIAL DEGENERATION 261 

exertion the pressure is increased, but afterwards becomes 
subnormal. The pressure is lowered during rest and sleep, 
but raised during mental exertion. 

By means of a hemodynamometer (Oliver) the arterial 
pressure can also be measured, the record being made on a 
dial. This is also used for observing venous pressure. 

On the Causes of Arterial Degeneration. — The occurrence 
of tuberculous or syphilitic arteritis is simply explained as an 
infection of the arterial wall by the specific infective agent. 
The explanation of the occurrence of arterio-capillary fibrosis, 
and of atheroma, the other form of angio-sclerosis, is not so 
easy. Arterio-capillary fibrosis is associated with chronic 
renal disease, and has not been observed in any other condi- 
tion. The muscular hypertrophy and fibroid thickening of the 
arterioles are probably to be ascribed to the irritant effect of 
some poison, although this has not been discovered. Atheroma 
is a degenerative process. It is difficult to see how it can be 
a compensatory process, as considered by some. The affection 
of the intima of the artery, and subsequently of the middle 
coat, would be due either to an effect on the inner wall of 
the vessel, or to an effect on the arterial blood supply of the 
Avail of the artery. 

As predisposing or leading causes in the production of 
atheroma, old age, strain, alcohol, lead, syphilis, and gout, have 
"been instanced. Strain might act by increasing, within long- 
periods, the tension inside the artery; gout and alcohol by 
producing deficient nutrition of the tissues. Syphilis, again, 
may act by producing disease of the vasa vasorum. 

The effect of continual increase of blood pressure in 
producing atheroma is seen in its occurrence in cases of 
granular contracted kidney. Many cases of atheroma occur 
without granular contracted kidney, and in these cases the 
disease may be localized. Thus, in individual cases, the first 
part of the aorta may be alone affected, or the whole of the 
aortic trunk, the peripheral arteries alone, or the arteries at 
the base of the brain. In such cases, in the absence of anv 
high arterial pressure, there must be some other element 



262 CHANGES IN THE CIRCULATION IN DISEASE 

besides strain in the production of the arterial degeneration. 
How far syphilis may be a cause is not yet determined. In 
any case, it can only be considered a predisposing cause, as 
atheroma itself is not a syphilitic lesion. 

The influence of increased pressure is observed in atheroma 
of the pulmonary artery and its branches, which occurs in long- 
standing cases of mitral stenosis, where a high pulmonary 
arterial pressure has been maintained for a long period. 






CHAPTER IX 

CHANGES IN THE CIRCULATION 

Edema and Dropsy. 

Edema and dropsy may be defined as a collection of fluid in 
the connective tissues and cavities of the body, and in certain 
of the organs, such as the lungs, brain, and intestines; it is 
not observed in the liver, kidney, or spleen substance, or in the 
spinal cord. It may be either local, affecting a limb, part of the 
lungs or brain, or one body cavity — such as the abdomen; or 
it may be general, in which case it either affects the subcuta- 
neous tissues chiefly (anasarca), or the cavities of the body 
chiefly, as well as the subcutaneous tissues. 

Local edema is observed in pressure on veins, in thrombosis, 
and in inflammatory areas. General edema is observed in 
morbus cordis, in anemia, in cachexia, and in Bright's 
disease. 

Edema of the pericardium is called hydropericardium ; of 
the pleura, hydrothorax; and of the peritoneum, ascites. The 
pericardium normally contains a small amount of fluid, and 
small quantities are present in the pleura and peritoneum. 
Connective tissues contain lymph, a fluid derived from the 
capillaries and the tissues, but this does not collect normally 
in the tissues, and is reabsorbed partly by the lymphatics and 
partly by the venous capillaries. 

Chemical Composition of the Lymph and other Similar 
Fluids. — The composition of lymph may be contrasted with 
that of plasma in the following table, in which the composi- 

263 



264 CHANGES IN THE CIRCULATION 

tion of human lymph, of lymph from the thoracic duct of the 
dog, and of blood plasma, is given : 



Total solids . . . 

Proteids . . . . 

Fibrin . . . 

Other proteids 

Extractives . . . 

Sugar . . , 

Urea . . . , 

Inorganic Salts . , 



Blood Plasma. 



Grams per cent. 
9.71 



O.405 

7.884 
O.566 

0. i to 0.15 
0.009 

0.855 



Human Lymph. 



Lymph from 

Thoracic Duct 

(Dog). 



I.366 
o 107 

O.23O 
O.13I 
O.I 

0.016 (dog) 
0.878 



3-7 to 5.5 
3.4 to 4.1 



0.8 to 0.9 



It is important to note that the composition of lymph varies 
considerably, according to the part of the body from which it 
is obtained, and this more particularly affects the percentage 
of proteids present. Thus, from the limbs the lymph contains 
2 to 3 grams per cent, of proteids; from the intestines, 
4 to 6 per cent. ; and from the liver 6 to 8 per cent. Like 
blood plasma, lymph coagulates spontaneously — sometimes 
slowly, sometimes rapidly. It contains cell elements and 
leukocytes. The composition of chyle differs from that of 
lymph mainly in the presence of a larger amount of total 
solids, and the larger proportion of proteids and of fat. (See 
Table, p. 266.) 

Composition of Edema and Dropsical Fluids. — These are 
all alkaline, and yellowish or yellowish-green, from the presence 
of a lipochrome. The specific gravity varies between 1010 
and 1 01 5; and in long-standing cases — more particularly of 
ascites — the specific gravity may be much lower. These 
figures contrast with the specific gravity of blood, which is 



COMPOSITIOX OF DROPSICAL FLUIDS 265 

1060; of blood plasma, which is between 1026 and 1029; and 
of inflammatory exudations, which is 1 01 8 or over. 

Dropsical fluids do not coagulate spontaneously, unless 
serum or blood be added. They contain a few cell elements, 
or these may be entirely absent. In their want of coagula- 
tion and the absence of the cell elements, they contrast with the 
normal lymph. 

The substances which are present in the dropsical fluids 
are the same as those which exist in lymph, but in different 
proportion : thus, of proteids, fibrinogen, serum globulin, and 
serum albumin are found; of extractives, cholesterin and 
sugar; while the salts are like those of the blood and in about 
the same proportion. The composition differs from that of 
lymph and blood plasma chiefly in the proportion of the total 
proteids present. Thus, blood serum contains from 5 to 6 per 
cent, of total proteids; the fluid in hydrothorax, from 0.8 to 2 
per cent. : ascitic fluid, from 0.03 to 0.8 per cent, (or an aver- 
age of about 0.4 per cent.) ; the fluid of subcutaneous edema, 
0.2-0.6 per cent.; hydrocele fluid, 0.5 per cent. (p. 9). Al- 
though, in all instances, the total proportion of proteid present 
in dropsical fluids is less than in lymph, the actual amount 
found in the fluids from one region in different cases varies 
considerably, and nowhere more than in the case of ascitic 
fluid, in which, sometimes, only traces of proteid are found, 
while, at other times, there is a considerable quantity 

In considering the lower proportion of proteid in dropsical 
fluid as compared with lymph, the composition of the blood 
in the particular case of disease must be taken into account, 
as well as other factors to be presently discussed. 

In Chylous Dropsical Effusions, such as chylous ascites and 
chylous hydrothorax, the composition of the fluid differs from 
those just considered, owing to the large proportion of fat 
present. In clear dropsical effusions only a small proportion 
can be obtained, about 0.034 per cent. ; whereas, in chylous 
effusions, the amount of fat varies between 0.9 and nearly 
2 per cent. This is shown in the following table, in which 
the percentage composition of chylous effusions is compared 



266 



CHANGES IN THE CIRCULATION 



with that of chyle and of a specimen of ascitic fluid, compara- 
tively rich in proteids : 





Human 

Chyle. 


Chyle of 
L>og. 


Serum of 
Dog. 


Chylous 
Ascites. 


Ascitic 
Fluid. 


Specific Gravity . 








IOI2 to I022 


1010 to 1015 


Total Solids . . 


4.1 to 5.6 


9.623 


6.399 


5.2 to 7 


1.55 


Proteids . . . 


1.1 to 1.3 


2.2l6 


4-524 


1.9 to 4.46 


0.617 


Fat, Cholesterin, j 
and Lecithin ) 




•• 


•• 


0.93 to 1.993 




Other Organic) 
Substances ) 




O.234 


O.291 




0.024 


Salts 


0.625 


O.792 


O.876 


0.48 to 0.7 


0.846 



The amount of sugar both in chyle and chylous fluid 
varies considerably. 

The comparison of chylous ascites with ascitic fluid shows 
that it bears the same relation in composition as chyle does 
to serum, inasmuch as it contains a much larger proportion of 
proteids and a much larger proportion of fats. This is due 
to the direct mixture of chyle with ascitic fluid. The fluid 
of chylous hydrothorax is practically of similar composition 
to that of chylous ascites. 

The Normal Formation of Lymph and its Functions. — 
Lymph is a part of the fluid portion of the blood which is 
passed out of the capillaries, and so has become extravascular. 
It is collected, no doubt, in the main, in the lymph spaces 
of the tissues, and soon passes into the lymphatic system 
and through the thoracic duct into the venous system. Part 
of it is also collected by the venous capillaries and so enters 
the venous system directly. The lymph in the lower part 
of the body mixes, in the thoracic duct, with the lymph from 
the liver and from the intestinal tract; and, as has already 
been stated, the lymph from the limbs contains less proteid 
than that coming from the liver. 

It has been much debated whether the formation of lymph 



FORMATION OF LYMPH 267 

is due to a process of filtration and osmosis from the blood 
capillaries (Ludwig) ; or whether it is a secretion of the en- 
dothelial cells of the capillaries (Heidenhain). In the first 
case, the formation of lymph would be, in great part, de- 
pendent on the intravascular pressure, more particularly the 
blood pressure in the capillaries. The greater the increase 
of intracapillary pressure, the greater the amount of lymph 
which would leave the vessels. In the second case, the for- 
mation of lymph would be dependent not so much on the 
intracapillary pressure as on the secretory activity of the 
endothelial cells of the capillaries. The conclusion that the 
lymph was probably a secretion rested on experiments which 
were directed to show, not only that an increased formation 
of lymph was independent of the intracapillary pressure, 
but that the injection of certain substances (lymphagogues) 
into the body caused an increased flow of lymph in the thoracic 
duct, varying in composition according to the substances used. 
Thus it was found that, associated with the great fall of 
arterial blood pressure in the vessels below complete obstruc- 
tion of the thoracic aorta, there was, practically, no 
alteration in the flow of lymph from the thoracic duct. 
Obstruction of the inferior vena cava above the dia- 
phragm causes a general fall of blood pressure, with a 
greatly increased flow of lymph from the thoracic duct; 
whereas, obstruction of the portal vein causes an increased 
flow of less concentrated lymph. 

Lymphagogues are divided into two classes. In the 
first, the injection of such substances as commercial peptone 
and leech or crayfish extract, causes an increased flow of 
concentrated lymph through the thoracic duct. Although the 
action of these substances is also to produce a fall of arterial 
blood pressure, yet the increased flow of lymph occurs even 
if the pressure is not lowered. In the second class, the injection 
of sodium chlorid, sugar, and potassium iodid in concentrated 
solution causes an increase of thin lymph, without any appre- 
ciable rise in the arterial pressure. These results, which at 
first appear to be in favor of the secretion hypothesis, are, 
however, better explained by the idea that the process is one 



268 CHANGES IN THE CIRCULATION 

of filtration (Starling). It has been shown that the increased 
flow of lymph on the ligature of the portal vein is due directly 
to the increased pressure in the capillaries of the portal system, 
the pressure being so great that not only large hemorrhages 
occur in the mucous membrane of the intestine, but red cor- 
puscles are present in the lymph. In obstruction of the 
vena cava just above the diaphragm, the increased flow of 
lymph in the thoracic duct, with an increased percentage of 
solids in the lymph, is due to increased lymph production 
from the highly permeable capillaries of the liver; the lymph 
does not come from the intestines. This case, again, is an 
instance of increased capillary pressure, which produces a 
greater effect in the liver than it does in the intestines. 
Again, in cases in which the aorta is obstructed, although 
there is a great fall of arterial pressure, which would influence 
considerably the capillary pressure in the intestines, there 
is but little alteration in the pressure in the hepatic capil- 
laries; and that the increased flow of lymph is due to the 
changes in the liver is shown by the fact that ligature of the 
hepatic lymphatics stops the flow of lymph in the thoracic duct 
when the thoracic aorta is obstructed. 

With regard to the action of the so-called lymphagogues, 
it may be said that the injection of the saline lymphagogues 
into the circulation causes an increase in the volume of the 
blood, owing to osmosis, the water of the tissues being at- 
tracted into the blood stream. This plethora leads to an 
increase in the capillary pressure, and to this is most prob- 
ably to be ascribed the increased flow of lymph, inasmuch 
as bleeding carried out previous to the injection of the lympha- 
gogue prevents the increased flow of lymph, the water which 
dextrose or salt attracts from the tissues into the 
blood being just sufficient to bring up the volume of 
the blood to the normal. 

The action of Heidenhain's first class of lymphagogues is 
not so readily explained. The increased flow of lymph' 
following the injection of leech extract does not appear to be 
dependent on a rise of capillary pressure; for, although this 
rise of capillary pressure does occur, especially in the portal 



CAUSES OF EDEMA 269 

system, it is only temporary, while the increased lymph flow 
lasts about three times longer. These substances are poisons, 
which, injected into the circulation, may damage the endo- 
thelial cells, and it does not appear necessary to conclude 
that they stimulate secretion. They may, by damaging the 
endothelial cells, cause an increased permeability of the 
capillary wall. 

In discussing the causes of edema and dropsy in disease, 
it appears more reasonable to consider that the factors in the 
production of these conditions are an increased capillary 
pressure, an increased permeability of the capillary wall, and 
a condition of hydremic plethora, all of which are factors 
which would lead to an increased transudation of lymph. 
But in edema, an increased transudation is not the only 
point. There may be diminished absorption of the lymph 
which is transuded, and this, theoretically, would have the 
same effect in the production of edema as an increased 
transudation. In edema and dropsy, however, an increased 
transudation of lymph from the capillaries is the main factor, 
diminished absorption of lymph from the tissues playing a 
subsidiary part. 

For the purpose of discussion these facts may be set forth 
in the following table (Starling) : 

Increased Transudation of Lymph is produced by — (a) An 
increased capillary pressure, which may be produced by: (1) 
venous obstruction: (2) vaso-dilatation; (3) plethora. 

(b) Increased permeability of the capillary wall, which may 
be produced by: (1) local injury, as in inflammation; (2) 
malnutrition, as in wasting diseases and anemias; (3) by 
poisons. 

(c) Hydremia, or a watery condition of the blood. 

Diminished Absorption of Lymph occurs: (a) through the 
lymphatics, as in paralysis of the limbs and obstructions of 
the large lymphatic trunks; (b) through the veins, as in 
venous obstruction, hydremia, and in concentrated transuda- 
tions. 

It is necessary to consider some of these points in detail. 

Venous Obstruction. — The obstruction to the flow of blood 



270 CHANGES IN THE CIRCULATION 

in the veins is a common factor in the production of edema 
and dropsy. Thus, it follows thrombosis of certain veins; 
for example, the femoral, and pressure on the large venous 
trunks, and occurs in stagnation of the blood in the right 
side of the heart from whatever cause. If the femoral vein 
of a normal animal be tied, no edema of the leg is produced. 
This is probably because the venous obstruction is not suf- 
ficient. If the vena cava inferior be tied, edema of both 
legs occurs, and a similar result follows the injection of 
plaster of Paris into the veins, as in Cohnheim's experiments. 
This accords very well with what is known of edema of the 
leg, following thrombosis of the femoral vein in disease. The 
thrombosis which occurs is not limited to the femoral vein, 
but is usually present in the smaller veins of the leg, so that 
the condition is comparable to the experiment of injecting 
plaster of Paris. An attempt was made to show that the 
production of edema of a limb with venous obstruction was 
in part dependent on the action of the vaso-motor nerves. 
Thus, as has been stated, ligature of the femoral vein causes 
no edema of the limb, but this ensues if the sciatic nerve be 
cut, or the vaso-motor nerves of the limb before they join the 
sciatic nerve (Ranvier). This, however, does not show that 
there is any special influence of the nervous system in the 
production of edema. The section of the sciatic nerve causes 
arterial dilatation, and so an increase in the capillary pressure, 
which has already been augmented by the tying of the vein. 
In the conditions of disease, in which venous obstruction is 
the main or sole cause of the edema, besides the increased 
transudation of lymph, there is also a diminished absorption, 
and this is brought about partly by the obstruction to the 
main venous trunk. Absorption by the lymphatics is also 
impeded, for the movement of the lymph in the limbs is 
dependent, partly on the suction power of the venous blood 
at the entrance of the thoracic duct into the jugular vein, 
but mainly on the movements of the limb; that is, the- 
muscles by their contraction press on the lymphatics in the 
fascia, so aiding the onward movement of the lymph. The 
obstruction to the vein and the impeded movements of the 



CAUSES OF EDEMA 271 

lymph, owing to the quiescence of the limb, are the chief 
reasons why the increased amount of fluid in the tissues is 
not removed. 

Lymphatic Obstruction. — Obstruction of the lymphatic 
trunks, causing a diminishing absorption of lymph, is not a 
common factor in the production of edema. This is mainly 
owing to the fact that the lymphatics freely anastomose, and, 
in the limb, it requires very extensive thrombosis of the 
lymphatics to produce edema, such as, in all probability, 
occurs in white leg. On the other hand, obstruction, throm- 
bosis, or pressure on the thoracic duct, may aid in the produc- 
tion of edema, though such obstruction is not infrequently 
followed by rupture. 

Increased Permeability of the Capillary Wall. — This must 
be considered one of the important factors in the causation 
of increased transudation of lymph. The capillary wall is 
composed of endothelial cells closely apposed to each other, 
and, though flattened, they are living and show some degree 
of contractility. There are no openings between the cells, 
and there is no evidence that, in disease, such openings or 
stomata are formed. The living capillary wall thus offers 
a considerable resistance to the passage of the albuminous 
plasma through it. There is some evidence that the per- 
meability of the capillary wall is not the same in all parts of 
the healthy body. Increased permeability of the wall is shown 
not only in the larger amount of liquid which is transuded, 
but in the larger proportion of albuminous substances that 
this liquid contains. The lymph from the limbs contains from 
2 to 3 per cent, of proteids; that from the intestine from 4 
to 6 per cent. ; whilst that from the liver contains from 6 to 
8 per cent. These facts may be taken as indicating that the 
liver capillaries are more permeable than the intestinal, and 
the intestinal capillaries than those of the limbs. 

In disease, increased permeability of the capillary wall is 
conceivably produced by direct injury — either mechanical or 
toxic — or by the malnutrition of the endothelial cells, which 



2 7 2 CHANGES IN THE CIRCULATION 

is due to defective nutritive properties in the blood, such as a 
watery condition (hydremia), or anemia. Thus, edema of 
the rabbit's ear follows an artificial anemia, produced by band- 
aging the ear. After the bandage is removed, the part 
becomes edematous, and, more particularly, if, in addition, 
the vein at the root of the ear is tied so as to increase the 
capillary pressure. The increased transudation in inflammation 
was ascribed to injury of the vessel wall by the poisons present 
in the inflamed area (p. 9) ; and this indeed seems to be the 
only explanation, the effect of the poisons on the capillary- 
wall leading to an increased permeability. 

Hydremia and Hydremic Plethora. — Hydremia is a term 
applied to the condition of the blood in which there is a 
deficiency of the solid constituents, both dissolved and floating. 
The total volume of blood is not increased. In hydremic 
plethora the volume of blood is greater than normal, while 
the watery condition of the blood is still present. A condition 
of hydremia alone might be supposed to aid the exudation 
of lymph by diminishing the proportion of proteids dissolved 
in the blood, and so aiding their passage through the capillary 
wall. This may be so, and instances of the occurrence of 
edema are recorded following the removal of blood, such as 
was frequently resorted to as a part of medical treatment in 
the early part of the last century. This empirical observation 
does not decide the part which hydremia plays in the pro- 
duction of edema, inasmuch as no accurate account was 
taken of the diseased condition for which venesection was 
performed. Bleeding a healthy animal leads to only a slight 
increase in the lymph flow and to no edema. If, however, a 
condition of hydremic plethora is produced, the lymph flow 
is enormously increased, and, with a very great degree of 
plethora, there is some edema of the internal organs, although 
not of the extremities. Hydremic plethora may be produced 
artificially by the intravenous injections of large quantities of 
normal saline fluid. The lymph flow is thereby increased over 
thirty times in a few minutes, but this effect is prevented if, 
previous to the injection of the saline fluid, the animal is bled 



LOCAL AND GENERAL EDEMA 273 

to the same amount. In hydremic plethora, however, it is 
not so much the condition of the blood which leads to the 
increased flow of lymph, as the increased capillary pressure 
which it causes. 

Edema and Dropsy in Diseased Conditions. — In disease, 
edema and dropsy may be either local or general. Examples 
of local edema and dropsy are : ( 1 ) Inflammatory edema. 
(2) Hydrocephalus. (3) Obstruction of the venous circulation, 
where this occurs as a result of blocking of, or pressure on, 
large veins, or as the result of embarrassment of the circu- 
lation in the right side of the heart. (4) Edema of the 
lungs, resulting from embarrassment of the pulmonary 
circulation. If the embarrassment at the heart is great, the 
edema may become general. (5) Local dropsy is also observed 
in anemia (chlorosis) and pernicious anemia, and in chronic 
diseases, with or without cachexia, and towards the end of 
the disease. It is observed in diabetes, and in the advanced 
stages of tuberculosis, malignant disease, and disease of the 
central nervous system. In these conditions the edema is 
almost solely confined to the lower extremities. (6) Angio- 
neurotic edema is a local condition occurring mainly in neu- 
ritis and neuralgia. 

General Dropsy is observed: (1) In embarrassment of the 
circulation on the right side of the heart, whether this occurs 
from disease of the mitral valve, or in the advanced stages 
of emphysema and bronchitis; and (2) in Bright's disease. 
In general dropsy, due to cardiac embarrassment, the sub- 
cutaneous tissues of the lower extremities are first affected; 
then those of the abdominal Avail. This is followed by ascites, 
hydrothorax. and hydropericardium. In the majority of 
instances, the upper extremities and the head and neck are not 
affected. In Bright's disease the edema due to the renal 
disease is general, and it first affects mainly the subcutaneous 
tissues of the limbs, trunk, head, and neck. In the later 
stages of chronic Bright's disease the general dropsy of 
the subcutaneous tissues and body cavities which occurs is 
mainly cardiac in origin. 
18 



274 CHANGES IN THE CIRCULATION 

In considering these examples of edema and dropsy from 
the point of view of their causation, it is obvious from what 
has been said that it is impossible to give any concise and 
accurate classification of the different conditions. In the 
causation of edema in a 'particular disease several of the factors 
which have been discussed operate. Two classes, how- 
ever, stand out as distinct: Inflammatory or Toxic Edema, 
and Obstructive Edema. A third class has been suggested, 
of Hydremic Dropsy, or edema associated chiefly with an 
altered condition of the blood. But, as has been shown, 
hydremia is not of itself a potent cause of edema, and, in 
including the edema of anemia, cachexia, and Bright's 
disease under the head of hydremic dropsy, it is evident that 
there must be some other cause than the hydremia to account 
for the condition. 

Venous obstruction dropsy is clear in its explanation. 
Thus, in the obstruction of a vein, the main cause of the 
edema is the increased capillary pressure, with the dimin- 
ished absorption previously discussed. In diseases of the heart 
edema is observed in disease of the mitral valve, which causes 
embarrassment of the circulation on the right side of the heart; 
and, in other conditions of dilatation of the right heart, 
whether the result of long-continued emphysema and bron- 
chitis, of aortic valvular disease (in the later stages), of 
adherent pericardium, or of a general dilatation of the 
heart due to disease of the myocardium. In all these condi- 
tions there is obstruction to the flow of venous blood through 
the heart, and, from this point of view, the causation of the 
edema may be said to be the same as in venous obstruction. 
Subsidiary causes, however, are to be noted. In prolonged 
disease, there is hydremia; there is also injury to the vessel 
wall, due to malnutrition, and there is the passage of a dimin- 
ished quantity of urine. 

In anemia, the edema occurs round the ankles and is 
rarely extensive. The changes in the blood may be said 
to predispose to edema by diminishing the nutrition of the 
endothelial cells, but the main cause is an increased capillary 
pressure in the legs, induced by the upright position. Thus, 



LOCAL AND GENERAL EDEMA 2 7 5 

the edema is observed at the end of the day, and disappears 
during the night, or with. rest. In the profound anemias, 
such as pernicious anemia, similar observations are made, 
but the edema is here frequently associated with a failing 
power of the heart. In cachectic conditions, besides a weakly 
acting heart, there is malnutrition of the vessel wall, caused 
by the changes in the blood, and leading to an increased per- 
meability. In Bright's disease, the explanation of the 
edema is not quite clear. Edema is observed in many 
cases of acute Bright's disease, and in chronic Bright's disease, 
in which there is a parenchymatous change in the kidneys. 
It is not observed, as a rule, in the granular contracted kidney 
associated with' high arterial pressure and hypertrophied heart, 
nor in the early stages of the lardaceous kidney. There is 
some relation between the occurrence of edema and the amount 
of urine passed. Thus, in the acute disease and in chronic 
parenchymatous nephritis, the amount of urine is greatly 
diminished, and edema is present. In the granular contracted 
kidney, with hypertrophied heart, and in the early stages of 
the lardaceous kidney, a large amount of urine is passed, 
and there is, as a rule, no edema. Although there is 
some relation between the amount of urine and the pres- 
ence of edema, yet the edema of Bright's disease cannot 
be ascribed to diminution in the amount of urine. When 
there is complete suppression of urine, as in the blocking of 
both ureters by calculi or in the experimental ligature of 
both ureters, there is no edema. Again, in acute Bright's 
disease, edema is not always present, although the urine may 
be greatly diminished and contain a large amount of albumin. 
The loss of albumin in the urine leads to a condition of 
hydremia, and the diminished amount of urine to a condi- 
tion of hypremic plethora; that is, to the retention of water 
in the blood. But this fact does not appear to offer a com- 
plete explanation of the edema of acute Bright's disease, and 
it is possible that the edema is associated with the circulation 
of poisons in the blood, and that it may be of the same 
nature as the inflammatory or toxic edema which is ob- 
served sometimes in infective disease. 



276 CHANGES IN THE CIRCULATION 

In chronic parenchymatous nephritis, the conditions of 
anemia and of hydremic plethora are important factors in 
the production of edema. In the granular contracted kidney, 
no edema is observed, while the left ventricle remains hyper- 
trophied and there is high arterial pressure. In this stage, 
a large quantity of urine is passed. When, however, from 
one cause or another, the diseased kidney becomes acutely 
or subacutely inflamed, edema is observed, and the urine 
diminishes. The cause of this edema is possibly the same 
as that of acute Bright's disease. Extensive edema occur- 
ring in chronic parenchymatous nephritis, and in the late 
stages of granular contracted kidney, is due to failure of the 
heart, producing the results previously described. 



CHAPTER X 

CHANGES IN RESPIRATION IN DISEASE 

Normal Respiration is carried out by means of the respira- 
tory apparatus, consisting of an impervious and elastic chest 
wall containing a cavity which is made larger by means of the 
muscles. Inside the cavity are the lungs, which are separated 
from the chest wall by the two layers of pleura. Expansion 
of the chest wall takes place by means of the contraction of 
the external intercostal muscles, and of the part of the internal 
intercostal which is between the cartilages. This expansion 
is permissible owing to the curve of the ribs, their down- 
ward slope, and their attachment by flexible cartilage to the 
sternum in front. The greatest degree of expansion is seen in 
the lower ribs. The muscles which aid expansion of the ribs 
are the scaleni, the levatores costarum, and the serratus posti- 
cus superior. An increase of the vertical diameter of the chest 
takes place by means of the contraction of the diaphragm, 
which flattens, and so increases the vertical diameter, mainly 
at the sides. The central tendon moves downwards a little. 
In man the respiration is more abdominal than costal; in 
woman the reverse is the case, and in them expansion of 
the upper part of the chest is more marked than of the lower. 
When the chest is enlarged in the manner described, the air 
remaining in the lungs (residual air) is rarefied, and so air 
enters the respiratory passages from outside, and expansion 
of the lungs takes place. Expiration is, unlike inspiration, 
not usually an active process. Both the chest and lungs 
return to their resting position by their elasticity. Expira- 
tion may, however, become an active process, as in speaking, 

277 



278 CHANGES IN RESPIRATION IN DISEASE 

singing, sneezing, coughing. The abdominal muscles are the 
chief ones contracting in forced expiration. They are aided 
by the interosseous part of the internal intercostals, and by 
the other muscles which depress the ribs. 

The number of respirations per minute varies somewhat 
in health between fourteen and eighteen; in infancy they 
are more frequent. Inspiration is somewhat longer than 
expiration. The term tidal air is given to the quantity of 
air which is changed in each respiration. In adults it is 
about 300 c. c. (20 cubic inches). The complemental air is 
the quantity above the tidal air which can be drawn into 
the lungs with the deepest inspiration: it is about 1600 c. c. 
(100 cubic inches). The supplemental air is the quantity of 
air above the tidal air which can be expelled by a forcible 
expiration. This is about the same in amount as the com- 
plemental air. The residual air is also about 1600 c. c. (100 
cubic inches), and is the air which always remains in the 
lungs after forced expiration. The sum of the complemental, 
tidal, and supplemental air is sometimes referred to as the 
vital or respiratory capacity. It is from 3500 to 4000 c. c. 
(225 to 250 cubic inches). 

The muscles concerned in respiration are voluntary muscles, 
and both the external intercostals and diaphragm can be con- 
tracted at will, although the normal expiration is involun- 
tary. The regular movements of the muscles in respiration 
are controlled by the respiratory center (nceud vitale) in 
the medulla. This center is partly automatic, but is mainly 
brought into action reflexly. Thus, in respiration, afferent 
impulses pass from the lungs by the vagus; efferent impulses 
pass from the center through the spinal cord to the muscles 
concerned in respiration. It is also affected by the higher 
centers of the brain, and reflexly through the sensory nerves 
of the body, not only those supplied to the respiratory tract, 
but those of the skin and of the internal organs. The respira- 
tory center is directly stimulated during life by the condition 
of the blood passing through it, the chief conditions of the 
blood being its temperature and the quantity of oxygen and 
carbonic acid contained in it. In normal conditions the object 



DYSPNEA 279 

of respiration is to obtain a sufficiency of oxygen with which 
to supply the tissues, and the intake of oxygen is propor- 
tionate to the needs (*. e., the activity) of the tissues. At 
rest and during sleep the respirations are less frequent and not 
so deep as when awake or when exertion is taken. 

From this short account of normal respiration it is evident 
that in disease the respiratory act may be altered in many 
different ways, not only by an affection of the respiratory 
apparatus, but also by an affection of the respiratory center 
and its nerve connections in one way or another. 

Disordered Respiration. — In disease, respiration may be 
increased in frequency or diminished. It may be irregular 
and shallow., or labored. The term dyspnea is used to indi- 
cate a condition of labored breathing, or increased fre- 
quency of respirations. From a pathological point of 
view it would be better to limit the term to conditions in 
which there is a difficulty in the passage of air in and out 
of the lungs — inspiratory dyspnea being limited to a con- 
dition in which there is a difficulty of the entrance of air 
into the lungs; expiratory, where there is difficulty of the 
exit of air from the lungs. From this point of view the term 
dyspnea would be practically limited to conditions in which 
there is some mechanical obstruction to respiration. The 
term, however, is not limited to these conditions, and it is 
more useful to consider it as including difficulty or increased 
frequency of respiration, with or without mechanical obstruc- 
tion. 

The respiratory act is affected in disease : 

1. By changes in the respiratory muscles and in the chest 
wall; by changes in the air passages and in the alveoli; and 
by changes in the chest outside the lungs, as in the pleura and 
mediastinum. 

2. By changes in the pulmonary circulation. 

3. By changes in the systemic circulation. 

4. By variations in the composition of the blood, such as 
a diminution of hemoglobin from whatever cause. 

5. By changes in the nervous mechanism of respiration. 



2 8o CHANGES IN RESPIRATION IN DISEASE 

These conditions are the primary cause of changes in the 
respiratory act. They lead to certain effects which are the 
direct cause of the changes in respiration. These direct causes 
are as follows : 

1. Deficiency of oxygen-containing air entering the lungs, 
and of oxygen in the blood. This must be considered the 
main direct cause of disorders of respiration. Whether the 
air contains less oxygen, or whether from one or other cause 
less air enters the lungs, the final result is the same, namely, 
a diminished quantity of oxygen in the blood, and so a dimin- 
ished quantity in the tissues. The same result is brought 
about, not by a diminished entrance of oxygen-containing air 
into the lungs, but by a diminished amount of hemo- 
globin in the blood. In this case, although oxygen is 
present, the hemoglobin is not in sufficient quantity to 
supply the tissues with a proper amount of oxygen. The 
changes observed in respiration as the result of these causes 
must be considered as directed to obtain more oxygen, for 
they are such as increased frequency of respiration and 
increased strength of respiration. In this class of cases, 
therefore, the changes observed in the respiratory act are 
directed to a beneficial end. 

2. A second class of direct causes of changes in respiration 
is an effect, reflex or direct, on the nervous center, whereby this 
is either stimulated, paralysed, or disordered. The result is 
either an increased frequency of respiration, a diminished 
frequency, or irregularity. The direct effect on the respira- 
tory center is due in one class of conditions to the action 
of poisons on the center, as in uremia, diphtheria, and other 
infective disorders, and such cases of poisoning as by snake- 
venom. A direct effect is also observed in disease of the 
brain; whether of the meninges, as in meningitis, or of the 
brain substance, as in cerebral tumor and the various forms 
of sclerosis. 

The changes in the respiratory act observed as the result, 
of these direct causes are due to changes in the respiratory 
center, which is stimulated by a deficiency of oxygen, or 
an increased amount of carbonic acid in the blood circulating 



CAUSES OF DISORDERED RESPIRATION 281 

through it, by the circulation of poisons through it, and by 
the direct effect of disease of the brain. 

Reflex irritation of the respiratory center also occurs : 
mainly through the vagus from the lungs and stomach, but 
also through the sensory nerves of the skin. The reflex 
effects are seen either in increased respiratory effort or in 
inhibition. 

I. Conditions of the Respiratory Apparatus Leading to Dis- 
ordered Respiration. — The conditions here to be discussed are 
mainly due to organic changes in one or other part of the 
respiratory apparatus, either the upper air passages, the tra- 
chea, the bronchi, the alveoli, the pleura and mediastinum, or 
the chest walls. These conditions have some changes in com- 
mon. These are (1) the deficient entrance of air into the 
alveoli — that is, inspiratory dyspnea with, in some cases, ex- 
piratory dyspnea. (2) The continuance of long periods of 
inspiratory dyspnea leads to deficient oxygenation of the blood, 
and so to deficient vitality of the tissues. (3) The effect of 
deficient entrance of air into the alveoli results in dyspnea 
or increased respiratory movements. This must be con- 
sidered as an effort to obtain more oxygen, and so as part 
of the mechanism of compensation. Compensation may be 
complete in some instances, but is usually partial. 

A. Direct Obstruction to the Entrance of Air into the 
Lungs. — (a) This occurs in naso-pharyngeal and laryngeal 
obstruction, and in stenosis of the trachea. The commonest 
example of naso-pharyngeal obstruction is seen in adenoid 
vegetations. The result of these is to produce an inspiratory 
dyspnea or labored inspiration. If long continued without 
treatment, the inspiratory dyspnea leads, with the soft chest 
walls of a child, either to a flattened chest or to a contraction 
of the base of the chest partly due to the more powerful action 
of the diaphragm in its endeavors to expand the chest 
properly. Xaso-pharyngeal obstruction may to some extent 
act reflexly on respiration by acting as an exciting cause 
of attacks of asthma in predisposed subjects. Laryngeal 
obstruction, whether flue to a spasm of the glottis, to 



282 CHANGES IN RESPIRATION IN DISEASE 

a pedunculated polypus, to diphtheria, or to edema of 
the glottis, causes inspiratory dyspnea. There is a prolonged' 
inspiration, frequently accompanied by a harsh noise or 
stridor, and an easy expiration. The prolonged inspiration^ 
is simply due to the fact that there is difficulty of entrance- 
of air through the obstructed part. Bilateral paralysis of the* 
openers of the glottis, the posterior crico-arytenoid muscles,, 
produces the same result as spasm of the glottis, (b) In 
stenosis of the trachea produced by disease, there is both in- 
spiratory and expiratory dyspnea; the number of respira- 
tions per minute is reduced, while the depth is increased, and 
stridor is frequently present. In experimental occlusion of" 
the trachea it is found that no dyspnea is present with a 
certain degree of stenosis, owing to the fact that the more 
powerful contraction of the respiratory muscles supplies the 
lungs with a sufficiency of air. This fact explains the absence 
of dyspnea in many cases of goiter, where the trachea is 
partly pressed upon. Severe dyspnea from stenosis of the 
trachea occurs in compression from both sides by a goiter, 
producing the so-called " sword-sheath " form of compression: 
With this there is softening of the cartilages. Diphtheria, 
stenosis from tertiary syphilis, and compression by an^ 
aneurysm, also lead to severe dyspnea. 

Obstruction of the air passages inside the lung is a fre- 
quent occurrence, and leads to both inspiratory and expira- 
tory dyspnea. Sudden obstruction of a large bronchus ex- 
perimentally produced may lead to pneumothorax, or to death 
from overstretching of the pulmonary capillaries. In disease, 
obstruction of a large bronchus is rarely complete. It leads 
to a diminished entrance of air into the part of the lung^ 
which it supplies, and apart from the infection of the bron- 
chial tube which results and which is not at present under 
discussion, it leads to partial or complete atelectasis (col- 
lapse) — that is, the air disappears from that part of the lung. 
This is due to absorption by the blood of the gases in the 
alveoli, the oxygen being absorbed first, the carbonic acid" 
next, and the nitrogen last. Obstruction of a large bronchus 
is produced by inhaled foreign bodies, by the pressure" 






CAUSES OF DISORDERED RESPIRATION 283 

of new growths or aneurysm, and by syphilitic stenosis. 
The degree of dyspnea which results from obstruction to a 
large bronchus depends on the power of compensation. Com- 
pensation occurs by dilatation of the unaffected alveoli, and 
by the increased activity of the respiratory muscles. In 
cases, however, where the chest wall is rigid, no dila- 
tation of the alveoli is possible, and with the weakened 
respiratory muscles increased attempts at contraction pro- 
duce but little effect. Compensation, therefore, is never 
complete. Labored respiration is present when the pa- 
tient is at rest in cases where there is no compensa- 
tion; while in cases of partial compensation there is no 
difficulty of respiration during rest, but only on exertion. 
•Obstruction of the small tubes produces an effect on respira- 
tion only when they are more or less universally affected.i 
This commonly occurs with the bronchitis of childhood and 
in some cases in adults. Atelectasis or collapse, following 
obstruction of the small tubes, is constantly seen. The 
broncho-pneumonia observed with it is a part of the infection, 
and not due simply to the obstruction of the tubes. 

Severe dyspnea due to obstruction of the small tubes is 
observed in asthma, a disease characterized by recurrent 
attacks of severe dyspnea without, for long periods, any 
sign of organic disease of the lungs. In the attacks of 
asthma the dyspnea is inspiratory, and to a less extent ex- 
piratory. Over the parts affected the respiratory murmur is 
absent, a fact strongly in favor of the condition being asso- 
ciated with a narrowing of the bronchioles due to a contraction 
of their muscular coats. As the attack passes off the respira- 
tory murmur reappears. 

B. Obstruction to the Entrance of Air in the Spongy Lung 
Tissue may be due to consolidation or destruction of the 
lung, to edema, to new growths, or to pressure on the lung 
by fluid in the pleura, or a tumor in the mediastinum. 
The effect on respiration of these conditions depends on two 
factors. The first is the extent to which the alveolar tissue 
is destroyed, and the second is the rapidity of the diseased 
process. Thus an acute consolidation of the lung, such as 



284 CHANGES IN RESPIRATION IN DISEASE 

occurs in pneumonia, acute edema, and a rapid effusion of 
fluid or air into the pleura, leads to great dyspnea which is 
chiefly inspiratory. On the other hand, a tumor of the 
lung may destroy .a large part of the spongy tissue without 
causing marked difficulty of respiration, and so with cases 
of chronic tuberculosis of the lung and very slowly forming 
effusion in the pleura. The effect, therefore, is proportional 
to the rapidity of the disease as well as to the degree of 
destruction of the alveolar tissue and the capacity of com- 
pensation. The absence of marked difficulty of respiration in 
many cases of chronic tuberculosis of the lung, where the 
air-breathing capacity is diminished to a greater extent than 
in many cases of pneumonia with severe dyspnea, is due to 
several factors. The first is the dilatation of the alveoli in 
the more healthy parts of the lung (compensatory emphy- 
sema), and the second is the diminished needs of the tissues 
for oxygen. Metabolism of the tissues in these prolonged 
cases is diminished, and so less oxygen is required. Dyspnea, 
however, frequently appears on exertion, and it may be 
sudden and severe in onset, as when pneumothorax or pleural 
effusion occurs on the side of the chest least affected by the 
tuberculosis. 

C. The Condition of the Chest-wall and Muscles has an 
important effect on the modification of respiration in disease. 
An affection of the diaphragm or external intercostal 
muscles produces an inspiratory dyspnea, resulting in the 
presence in the lungs of too large a quantity of residual 
air. The muscles not acting sufficiently, the accessory 
muscles of respiration come into play, but this does not lead 
to the entrance of a sufficient quantity of air, and there is 
consequently a similar diminution in the amount of air 
expired. The tidal air being diminished, the residual 
air is increased. The movements of the diaphragm are 
more frequently affected in disease than those of the 
external intercostal muscles. The diaphragm may be im- - 
perfect, as in some cases of diaphragmatic hernia, or in rare 
cases it may be absent. A diminished contractility is ob- 
served in infective disease and in fatty degeneration, which 



CAUSES OF DISORDERED RESPIRATION 285 

occurs in prolonged cases of emphysema and bronchitis, in 
morbus cordis, in pernicious anemia, in chronic nerve disease, 
such as general paralysis of the insane (Cohnheim), and in 
wasting diseases. Its action may also be hampered by the 
invasion of new growths, or by the trichina spiralis, and it 
may be paralyzed by pressure on the phrenic nerves and in 
diphtheria, lead-poisoning, and hysteria. In great abdominal 
distention, whether from tumors or fluid, or in tympanites, the 
action of the diaphragm is greatly impeded; as well as in 
adhesions to the lungs or the abdominal organs. 

As has been said, inefficient action or paralysis of the 
diaphragm leads to inspiratory dyspnea. This, however, may 
not be present if the external intercostal muscles are 
vigorous, for costal respiration, replacing the abdominal, com- 
pensates for the loss of the action of the diaphragm. Even 
if the external intercostal muscles be intact, their power of 
compensating for the loss of the diaphragm depends on the 
presence or absence of rigidity of the chest. In ossification 
of the cartilages, the action of the external intercostals in 
expanding the chest is very limited. The external intercostal 
muscles themselves are not commonly affected in disease. In 
rare cases of peripheral neuritis they may be paralyzed, and 
in wasting diseases they are diminished like the rest of the 
muscles of the body. They are also atrophied in chronic 
disease of the lungs and pleura. 

Rigidity of the chest wall with the loss of elasticity in 
the lung tissue which occurs in emphysema leads to ex- 
piratory dyspnea, and so to a larger quantity of residual air. 
The result is an imperfect interchange of gases in the lungs, 
and, on exertion, dyspnea, both inspiratory and expiratory, 
is produced. 

II. Influence of the Pulmonary Circulation on Respiration. 
— This must be considered separately from the condition of 
the bronchial tubes or lung tissue, inasmuch as normal respira- 
tion depends on the regular exchange of gases between the 
air and the circulating blood in the lungs. If, therefore, 
sufficient blood is not brought to the lungs to be aerated, or 



286 CHANGES IN RESPIRATION IN DISEASE 

if there is a relative stagnation of the blood in the lungs, the 
aeration of the systemic blood is deficient. The result is 
increased respiratory movements, owing to stimulation of the 
respiratory center. 

(i) The amount of blood brought to the lungs may be 
deficient, either as a whole, as in pressure on the pulmonary 
artery, or in part, as in local disease of the lungs. This partial 
deficiency occurs in cirrhosis of the lung, in embolism of a 
large branch of the pulmonary artery, in chronic tuberculosis, 
and in emphysema, in both of which cases the vessels of the 
lung may be destroyed, and it is also seen in pressure on the 
lung, as by gas or fluid in the pleura, or by tumors. The 
pulmonary circulation is also affected in completely adherent 
pleura, in extensive collapse of the lung tissue, and in chronic 
bronchitis. The direct cause of the dyspnea in these condi- 
tions is the deficiency of oxygenated blood in the respiratory 
center. The increased movements of respiration which occur 
are beneficial in so far as they tend to introduce more air 
into the lungs, and so produce a more rapid interchange of 
gases. 

(2) Embarrassment of the pulmonary circulation due to 
morbus cordis leads to disordered respiration. In failure of 
compensation, more particularly in mitral disease, there is a 
diminished contraction of the right ventricle; and in stenosis 
of the mitral valve there is in addition an increased resist- 
ance to the entrance of the blood into the left ventricle. 
This leads to an increased arterial pressure in the pulmonary 
circulation; the relative stagnation of blood diminishes the 
interchange of gases, and the direct cause of the increased 
respiratory movements is, as in the first class of cases discussed, 
a deficiency of oxygenated blood in the respiratory center. 
The dyspnea occurring in morbus cordis from embarrassment 
of the pulmonary circulation is not so evidently beneficial as 
in the first class of cases considered. By some it is con- 
sidered of little use, inasmuch as the respiratory exchange is 
not increased by the increased movements of respiration, 
mainly owing to the slow blood current through the lungs. 
The respiratory movements may, however, be considered to 



CAUSES OF DISORDERED RESPIRATION 287 

have one useful effect, namely, in causing the blood to flow 
more rapidly from the systemic veins into the chest. 

Compensation for disordered respiration due to defects in 
the pulmonary circulation takes place by means of hyper- 
trophy of the right ventricle of the heart. 

III. Influence of the Composition of the Blood and the 
Presence of Poisons on the Respiration. — (1) Influence of 
Composition of the Blood. — A diminution in the proteid and 
other soluble elements of the blood would affect the vitality 
of the respiratory center, rendering it, perhaps, in the early 
stage, more irritable to stimulation, and, in the later stage, 
less irritable; but the condition of the blood which is more 
closely concerned with disordered respiration is the presence 
of a diminished quantity of hemoglobin. In this case, although 
the respiratory apparatus and nervous mechanism may be 
normal, there is an insufficiency of oxygen in the blood and 
in the tissues, owing to the fact that there is not sufficient 
hemoglobin to combine with the oxygen. Thus the respira- 
tory center is stimulated to action by deficiency in the amount 
of oxygen carried to it, and dyspnea results. The increased 
respiratory movements have no marked effect in remedying 
the condition, as, although the oxygen in the lungs is suffi- 
cient in quantity, the hemoglobin in the blood is deficient 
(see Chapter XVII.). In moderate degrees of anemia, such 
as are observed in chlorosis and in some forms of secondary 
anemia, the dyspnea is not observed when the body is at 
rest, only on exertion. In profound anemia, such as is seen 
in pernicious anemia and in severe secondary anemias, the 
difficulty of respiration (besoin de respirer) exists with the 
body at rest. This is a " deficiency of oxygen " dyspnea. 

(2) The Circulation of Poisons in the Blood may lead to 
disordered respiration and dyspnea by a direct effect on the 
respiratory center. Some poisons lead to dyspnea by causing 
stagnation of the pulmonary circulation, but this effect is not 
observed in those under consideration. Uremic dyspnea 
(renal asthma) may be quoted as an example of this form 
of disordered respiration, although the question of a uremic 



288 CHANGES IN RESPIRATION IN DISEASE 

poison is not yet settled. This form of dyspnea is not 
associated with embarrassment of the pulmonary circulation. 
It may be associated with an increased systemic arterial 
pressure, but its most important association from the present 
point of view is that with definite nerve symptoms, such as 
headache, twitchings, convulsions, and coma; a series of 
symptoms which indicates the action of some agent or agents 
on the brain. The dyspnea may be continuous or intermittent, 
occurring in definite attacks, like those of asthma, but without 
the cyanosis or other sigtas accompanying that condition. It 
is relieved in some cases by the removal of blood, or by the 
administration of nitrites which dilate the peripheral vessels, 
or by purgation. 

Some of the poisons of infective disease act directly 
on the respiratory center. To such an action must be ascribed 
the attacks of dyspnea which occur in diphtheritic paralysis 
and in the later stages of acute diphtheria-. Snake-venom and 
abrin also apparently have a direct effect on the respiratory 
and other centers in the medulla. 

IV. Influence of the Nervous System on Respiration in 
Disease. — The physiological relations of the respiratory center 
have already been discussed (p. 278). Its activity is dimin- 
ished normally when the blood circulating through it contains 
a diminished quantity of oxygen or an increased quantity of 
carbonic acid. After birth it is the stimulation of the center 
by the diminished quantity of oxygen which causes at first 
independent respiratory movements of the newly born child. 
In disordered respiration the influence of the quality of blood 
is of great importance, and has been previously discussed. 
The respiratory center may in disease, however, be affected 
by conditions other than that of the quality of the blood sup- 
plied to it, and it may show the results either of abnormal 
stimulation or of a diminished excitability. 

Abnormal stimulation and excitability of the respiratory 
center is observed in hysterical dyspnea, in neurotic asthma,' 
in uremia, in ligature of the vessels supplying the brain, 
and when blood at an abnormally high temperature passes 



CHEYNE-STOKES BREATHING 289 

through it. It is evident that the two first conditions are 
separable pathologically from the three last, inasmuch as in 
both hysterical dyspnea and neurotic asthma there is a 
functional disturbance of the respiratory center not associated, 
as far as is known, with any abnormal condition of the 
blood supplied to it. In both these functional conditions 
there is some evidence that the actual dyspneic attack 
results from the stimulation of the center by a peripheral 
irritation, some local condition in the respiratory tract or 
internal organs. 

A diminished excitability of the respiratory center is 
observed in disease of the brain, such as tumors, hemorrhage 
(especially when affecting the medulla), and meningitis, also 
in long-continued febrile disease or chronic diseases of the 
respiratory organs. In this class, as in the first, the affection 
of the respiratory center by brain disease is not directly 
associated with any change in the quality of the blood 
supplied to the center, though this is probably the case with 
long-continued pyrexia, or with hyperpyrexia, and with chronic 
diseases of the respiratory tract. 

Cheyne-Stokes Breathing (Fig. 88.) — Periodic Respira- 
tion. — This is a peculiar form of breathing which is best de- 




Fic. 88.— Tracing of Cheyne-Stokes respiration. (Pembrey.) 

The tracing shows the periodic character of the respiration. The 
respiratory acts are grouped, and the groups are separated by a period 
of absence of movement. When respiration begins again, the first is 
short, and the movements gradually acquire a maximum, after which 
they fall, and another period of rest ensues. (Kirke's Physiology.) 

scribed as periodic respiration. It consists of a series of inspira- 
tions increasing to a maximum (dyspnea), then declining until 
the respirations cease: a pause (apnea) preceding the recurrence 
of the phenomenon. Four or five periods of respirations with 
pauses may occur in the course of one minute. In some 
cases a pause lasts thirty or forty seconds, the respirations 
'9 



290 CHANGES IN RESPIRATION IN DISEASE 

lasting about the same period. Periodic respiration is ob- 
served physiologically in hibernating animals, and respirations 
with pauses are observed in some children during sleep. It 
is also seen in disease: in disease of the brain, such as tu- 
mors, hemorrhage, meningitis, and anemia; and in disease 
of the heart, such as fatty heart, sclerosis of the coronary 
arteries, and stenosis of the aortic valves. It is always as- 
sociated with severe illness, and usually appears before its 
fatal termination. Experimentally, it may be produced by 
the injection of morphin into the veins of rabbits and dogs, 
by the injection of magnesium sulphate into dogs, or by lig- 
ature of the vessels supplying the brain. 

The explanation of the phenomenon is not easy, but the 
chief pathological condition seems to be one of diminished 
irritability of the respiratory center. The center appears to 
be in a dying condition. The increase of respirations leading 
to dyspnea appears to be brought about by a diminished ar- 
terial blood supply to the center, the deficiency of oxygen 
stimulating the center to increased activity for a time. It 
soon, however, gets exhausted, hence the decline of the 
respirations and their final cessation. After a certain period 
of rest the center regains its activity for a time, and the 
phenomenon is repeated. Cheyne-Stokes breathing experi- 
mentally produced is relieved by the administration of amyl 
nitrite, which dilates the blood vessels (Filehne). 

A similar phenomenon in the circulatory system is observed 
in Traube's curves, which are undulations in the arterial blood- 
pressure curve which gradually diminish in size until the 
heart ceases beating. Traube's curves are ascribed to ex- 
haustion of the vaso-motor center in the medulla. 

Means of Compensation in Disorders of Respiration. — As 
has been shown in the previous pages, disordered respiration 
may be due to several factors which include defects of the respi- 
ratory apparatus, defects of the pulmonary circulation, as well | 
as changes in the composition of the blood and in the condition 
of the central nervous system. It has also been pointed out 
that several factors may be present in each individual case, 






MEANS OF COMPENSATION 291 

and it is important to determine the presence of these factors 
in order to judge how far compensation is possible. In some 
instances of disordered respiration the increased respiratory- 
movements are directed to the removal of the condition pro- 
ducing the dyspnea, while in other conditions — chiefly 
nervous and toxic in origin — the disordered respiration is 
purposeless in character. 

Compensation takes place mainly when the disordered 
respiration is due to a defect in the respiratory apparatus 
and in the pulmonary circulation. 

1. Compensation in Defects of the Respiratory Apparatus. — 
When there are any of the defects in the respiratory 
apparatus previously discussed (p. 281), compensation takes 
place by means of the enlargement of the lungs, either 
generally or, more commonly, locally. This is referred to as 
compensatory emphysema, and consists in the dilatation of the 
healthy alveoli, whereby they contain more air. It has been 
doubted whether in some cases the filling of the alveoli with 
more air means an increased respiratory exchange. It may, 
however, possibly mean this, as its occurrence in cases of 
chronic pulmonary tuberculosis must be considered as bene- 
ficial. It is said that a true hypertrophy of the lung is pos- 
sible. It is difficult, however, to see how there can be a for- 
mation of new alveoli. 

The second means of compensation is the action of the 
accessory muscles of respiration, such as the sterno-mastoids, 
the scaleni, the serrati, and the muscles passing from the chest 
to the upper limb. These, by more firmly fixing the upper 
part of the chest, facilitate the expansion of the middle and 
lower part of the thorax by the external intercostal muscles. 
This action of the accessory muscles is, however, of but little 
avail if they have been weakened by disease, or if the chest 
be rigid, as in old age. 

Hypertrophy of the respiratory muscles occurs as an aid 
in compensation. Dyspnea, or labored respiration, must be 
considered itself a compensatory process; inspiratory dyspnea 
in order to get more air into the lungs; expiratory dyspnea 
to expel more air. With labored inspiration not only is 



292 CHANGES IN RESPIRATION IN DISEASE 

more oxygen taken into the lungs, but the pulmonary 
circulation is increased, owing to the inspiratory action 
of the chest. 

2. Compensation in Defects of the Pulmonary Circulation. — 
In cases where there is retardation of the blood in the lungs, 
or where (as in emphysema) there is difficulty in the passage 
of blood through the lungs, compensation for the disordered 
respiration produced occurs by means of hypertrophy of the 
right side of the heart. This, by increasing the force of circu- 
lation through the lungs, tends to relieve the disordered respi- 
ration by increasing the respiratory exchange. 

3. A third method of compensation occurs in certain chronic 
diseases of the respiratory apparatus. Thus, in chronic cases 
of pulmonary tuberculosis, where the air-breathing capacity 
of part of a lung is destroyed, there may be no dyspnea. 
This may occur also in extensive pleural adhesions, in slowly 
advancing pleural effusion, and in tumors of the lung, as 
well as in emphysema and in bronchiectasis. In these con- 
ditions there may be no dyspnea when the patient is at 
rest, although the air-breathing capacity of the lungs is 
diminished. Dyspnea, however, supervenes on exertion, or if 
a complication be present, such as disease of the mitral valve 
and pneumo-thorax or pleuritic effusion compressing the more 
healthy part of the lung. Such conditions last for many 
months or years, and the organism adapts itself to a 
diminished oxygen supply. The total metabolism of the 
body is diminished, owing to the diminished quantity of 
oxygen present in the blood, but a disordered respiration is 
not seen, inasmuch as the tissues receive sufficient oxygen, 
when the body is at rest, to carry on their functions. 
Continued deficiency of oxygen, however, leads to tissue de- 
generation, such as fatty degeneration (p. 202). 

Cyanosis. — The result of want of compensation in dis- 
ordered respiration is cyanosis, in which there is blueness of; 
the extremities, and of the face, ears, and nose. In cyanosis the 
blood in the capillaries parts more completely than normal with' 
the oxygen and takes up more carbonic acid. Receiving a 
diminished quantity of oxygen from the air in the lungs, the 



ASPHYXIA 293 

oxygen contents of the blood are not renewed. Marked 
cyanosis is prevented by a general anemia, as in chronic 
tuberculosis of the lungs. It is seen, however, in acute 
tuberculosis. 

Asphyxia or Suffocation. — Asphyxia occurs either from 
some sudden stoppage of the entrance of air into the lungs, 
or stoppage of the pulmonary circulation, or is the final 
result of one or other of the chronic respiratory defects 
previously described. Rapid asphyxia occurs in edema of 
the lungs, in hemorrhage into the bronchi, in embolism of 
the pulmonary artery, in spasm and edema of the glottis, and 
in double pneumothorax, as well as in the sudden compression 
of the trachea by a goiter. 

In acute asphyxia two stages are recognized. In the first 
there is a rise of blood pressure accompanied by labored 
breathing, restlessness, and clonic convulsions. In the second 
there is a fall of blood pressure, and this is accompanied by 
a cessation of respiration and ends in death, the heart beat 
being continued for a short time after the breathing has 
ceased. The effect in acute asphyxia is due to the cutting 
off of the supply of oxygen. 

Slow suffocation is observed as the termination of the respi- 
ratory defects previously discussed and ends in death. There 
is labored breathing with restlessness, and usually a fall of 
blood pressure; clonic convulsions are usually absent, but to- 
wards the end of life, when the respiration is becoming shallow 
and rapid, twitchings of the muscles may be observed. 

Failure of compensation in chronic respiratory defects may 
be due to an extension of the original disease, such as 
occurs in chronic pulmonary tuberculosis, to weakness of the 
muscles of respiration, either from exhaustion or fatty 
degeneration, or to the invasion of an infective disease 
causing pyrexia, which weakens the muscles and diminishes 
the activity of the respiratory center, as well as to a pro- 
gressive anemia. 

Modified Respiratory Acts. — Cough, Sneezing, Hiccough. — 
Cough. — An active cough is preceded by a deep inspiration and 






294 CHANGES IN RESPIRATION IN DISEASE 

accompanied by a sudden expiration due to the spasmodic 
contraction of the abdominal muscles. During this explosive 
expiration the glottis, previously closed, is forced open by the 
rush of air due to the sudden compression of the lungs. Cough 
is a reflex act, and the afferent impulses to the respiratory 
center are carried by branches of the vagus — chiefly by the 
superior laryngeal nerve to the larynx, and by other branches 
to the bronchial mucous membrane, to the alveolar tissue of 
the lung, to the pleura, and to the external auditory meatus. 
Cough may also be excited through the sensory nerves of the 
skin, as by the application of cold. The parts most sensitive to 
peripheral irritation in inducing cough are the larynx, the 
bifurcation of the trachea, and the bronchial tubes. The chief 
irritant exciting cough is the presence of excessive mucus or 
other secretion, or a foreign body, on the laryngeal or 
bronchial mucous membrane. 

Peripheral stimulation carried by the afferent nerves in the 
branches of the vagus supplied to the abdominal viscera 
(stomach and liver) does not excite cough, and there is no 
evidence of the existence of a " stomach " cough, that is, a 
cough excited by irritation of the branches of the vagus sup- 
plied to the stomach. When cough exists in stomach condi- 
tions it is usually due to the irritation of acid or other liquids 
and of gases irritating the larynx and the fauces. 

It is evident that in diseased conditions intensity of cough 
depends on three conditions: (i) The amount of peripheral 
irritation, which is equivalent to the amount and character of 
foreign matter to be expelled; (2) to the part of the respira- 
tory tract which is irritated; and (3) to the degree of 
irritability o*f the respiratory center. Thus a large amount 
of secretion present in the larynx or bronchial tubes will lead 
to excessive cough, more particularly if the secretion is of a 
tenacious character and with difficulty expelled. Excessive 
irritability of the respiratory center, which, in common with 
that of other centers, occurs in prolonged anemia and in 
wasting diseases, leads also to excessive cough, even a slight 
degree of peripheral irritation causing an excessive response 
from the respiratory center. Excessive cough is observed in 



COUGH 295 

laryngitis and bronchitis when the secretion of the inflamed 
mucous membrane is tenacious. The cough diminishes when 
the secretion becomes more liquid, and thus more easily 
expelled. In bronchitis, when the secretion is not tenacious, 
the cough is not excessive unless the secretion is so copious 
as to collect in the smaller tubes, and so leads to great diffi- 
culty of expectoration. This may occur during the day, but 
more particularly occurs at night during the period of sleep, 
thus leading to excessive cough in the morning on waking. 

The alveolar tissue of the lung when affected by disease 
is less productive of cough than the laryngeal or bronchial 
mucous membranes. Thus a large portion of the alveolar 
tissue of one lung may be consolidated without producing as 
much cough as a mild inflammation of the bronchial mucous 
membrane; a short dry cough is produced, not excessive and 
infrequent. A similar degree of cough is excited by inflam- 
mation of the pleura, but the pleura may be extensively 
diseased by a chronic condition without the production of 
any noticeable cough. An affection of the diaphragm itself 
does not lead to cough, except as regards the affection of the 
pleura accompanying it. 

Excessive cough which in some cases leads to a temporary 
cyanosis, to exhaustion, and to vomiting, occurs more particu- 
larly in irritative laryngeal conditions, in chronic bronchitis, 
and in tuberculosis of the lungs. In chronic bronchitis the 
excessive cough has been already partly explained as due to 
the accumulation of secretion in the bronchial tubes during 
the night, and to an excessive secretion during the day, as 
well as in other cases to the tenacious character of the 
secretion and the difficulty of expelling it. There is another 
factor, however, which occurs as a sequence of the repeated 
paroxysms of cough in chronic bronchitis, and that is the 
irritability of the respiratory center, induced by an irregularity 
of the blood supply. Thus the paroxysms of cough lead to 
a temporary diminution in the respiratory exchange of the 
lungs, and so to a passing cyanosis in which the respiratory 
center is affected like the other parts of the body. The 
temporary cyanosis is followed by a dyspneic condition, and 



296 CHANGES IN RESPIRATION IN DISEASE 

this irregular action of the respiratory center leads eventually 
to its disorganization, so that its irritability is increased. 

In chronic tuberculosis the center is also affected, its irri- 
tability being increased, but this is brought about in another 
manner. The anemia produced by the wasting disease leads 
to an impoverished blood supply to the center, and so to an 
increased irritability. Excessive cough, therefore, in chronic 
tuberculosis of the lungs is in the majority of instances due 
more to the irritability of the center than to accumulation of 
secretion in the bronchial tubes. 

Although it is stated above that there is probably no such 
condition as a " stomach " cough, yet cough may be excited 
by the presence of food in the stomach. Thus, in cases of 
chronic bronchitis and chronic tuberculosis of the lungs with 
cough, the occurrence of paroxysms of coughing after the 
ingestion of a large meal is a frequent occurrence. One 
possible explanation of this is that the presence of a large 
meal in the stomach leads to a diminution in the respiratory 
movements, and so to an accumulation of secretion in the 
lungs. But this is not the sole explanation, and it is possible 
that there is an afferent impulse from the stomach to the 
center in the medulla whereby the cough is induced. Vomit- 
ing not infrequently follows a paroxysm of coughing induced 
by a large meal, but the vomiting is in the majority of cases 
a mechanical act, the excessive action of the abdominal 
muscles during the respiratory act pressing on the stomach, 
and so leading to the vomiting. 

Sneezing. — Sneezing is the same kind of reflex act as in 
coughing, there being an explosive expiratory effort during 
which a current of air is directed through the nose, and not 
through the mouth, as in coughing. It is excited mainly by 
irritation of the nasal mucous membrane, either by a foreign 
body or by excessive secretion. It is in some instances 
excited reflexly through the eyes, as when a bright light 
causes sneezing. As in coughing, the degree of sneezing 
depends on the severity of the peripheral irritation as well as 
on the irritability of the respiratory center. Thus a simple 
act of sneezing occurring in the course of a common cold 



HICCOUGH 297 

may be contrasted with the excessive degree of sneezing 
which occurs in individuals subject to " hay fever/' and in this 
case the peripheral irritation of the nose leads not only to 
the special act (that is sneezing) with which the nasal mucous 
membrane is associated, but to dyspnea, producing " hay 
asthma." 

Hiccough. — Hiccough is due to a violent inspiratory con- 
traction of the diaphragm, which ceases by a sudden closure 
of the glottis. It is caused by reflex irritation from the 
stomach, especially in cases where the organ is irritated by 
over eating and drinking. It usually occurs in individuals 
with excitable nervous systems. It may also be produced 
from peripheral irritation of the peritoneum, as in peritonitis, 
especially when it affects the diaphragm. 



CHAPTER XI 

CHANGES IN THE BLOOD IN DISEASE 

I. Changes in the Red and White Corpuscles 

The changes which occur in the blood in disease are very- 
numerous, and may be grouped under the following headings : 
i. Changes in the red and white corpuscles, 2. Changes in 
the amount and distribution of the hemoglobin the former 
contain. 3. Changes in the coagulability of the blood and 
other chemical variations from the normal. 4. The presence 
of bacterial and animal parasites in the blood (Chapters III. 
andVL). 

Chemical variations other than coagulability are discussed 
under separate headings; they are such as changes in the 
amount of water, proteid, and other normal constituents, 
changes in the amount of sugar, and the presence of 
abnormal chemical substances. 

Changes in the Corpuscular Element of the Blood. — 1. The 
Red Corpuscles: Anemias. — Origin of the Red Corpuscles. — 
The red corpuscles are formed from the middle layer of the 
embryo, like the white discs. They are formed in two ways. 
Before birth they are intracellular in origin. In the protoplasm 
of the cell, spherical globules, varying in size, are formed, which 
eventually become adult corpuscles, the cell itself being de- 
veloped into a primitive blood vessel. Another mode of origin, 
which also continues through life, is from the red marrow. 
The Erythroblasts (Fig. 89) which are here formed are nucle- 
ated cells varying in shape, some being round, others oval, and 
some pear-shaped, while others again show a division of the 

298 



THE RED CORPUSCLES 299 

-nucleus. The nucleus disappears as the cell becomes trans- 
formed into the adult red corpuscle. 

• # $ m % &S I #•€ • 

Fig. S9. — Erythroblasts from the bone marrow. (Kirke's Physiology.) 
The figure shows the varying shape of the nucleated and immature red corpuscles 
as thev occur in the bone marrow. They vary in size and in shape, some being pear- 
shaped, others oval, and some showing division of the nucleus and commencing 
division of the cell. 

Structure of the Red Corpuscles. — When blood is shed, the 
-red corpuscles form into rouleaux, the concave surfaces of the 
discs being apposed to each other. They frequently become 
crenated, and under the action of water they swell, losing 
iheir biconcave shape and becoming more globular. The 
-average diameter varies between 6.6 >< and 8 w, or an average 
of 7.5 u. The average number of corpuscles is, in adult man, 
5,000,000 per cubic millimeter, and in adult woman, 4,500,000. 
The size, shape, rouleaux formation, and number of corpuscles 
are important points to be considered in diseased conditions 
of the blood. In addition, there is the relation between the 
amount of hemoglobin and the number of corpuscles. This 
is called the color index, and is the ratio between the per- 
centage of hemoglobin and the percentage of corpuscles. 
Thus, if the percentage of hemoglobin found in a particular 
instance is 30, and the percentage of red corpuscles is 80, 

the color index is -jr- =0.37. 

2. Normal Variations in the Red Corpuscles and the Amount 
of Hemoglobin. — The average number of corpuscles in adult 
life is fairly constant, and, as a rule, the amount of hemoglobin 
varies with the number of corpuscles. In the newly born, the 
red corpuscles are between 7,000,000 and 8,000,000 per cubic 
millimeter. Their number, however, diminishes within seven to 
ten days after birth. In healthy young men the normal number 
may be increased to 6,000,000 per cubic millimeter. In old age 
the red discs are sometimes, but not always, diminished. An 
increased number of corpuscles, up to 8,000,000, has been found 
in those living at high altitudes and this increase appears to 



3 oo CHANGES IN THE BLOOD IN DISEASE 

be proportional to the height above the sea level. In this 
case, the hemoglobin, although increased, is not proportionately 
so to the increase of the corpuscles. A diminution in number 
takes place on returning to life at a lower level. 

After a meal the red corpuscles are slightly diminished. 
Excessive fatigue causes a diminution; it may be of 500,000 
per cubic millimeter. The drinking of large quantities of 
liquid diminishes the corpuscular count. This is, on the other 
hand, increased by sweating and fasting, both of which lead to 
concentration of the blood. Menstruation, childbirth, and lac- 
tation diminish the number of corpuscles. 

Increase of the Corpuscles in Disease. — In cyanosis, whether 
local or general, an apparent increase in the number of cor- 
puscles (polycythemia) occurs, owing to the relative stagnation 
in the peripheral blood. A high corpuscular count may also be 
found in conditions in which the blood becomes concentrated. 
These conditions are usually temporary, and are such as pro- 
fuse watery diarrhea, profuse sweating, persistent vomiting, 
starvation of liquids, and large serous effusions. There is, 
however, no real increase in the number of corpuscles in these 
cases, the increased number counted being due to the concen- 
tration of the blood. A true polycythemia is said to occur in 
phosphorus poisoning, in which the red corpuscles have been 
found to be over 8,000,000 per cubic millimeter, and in car- 
bonic oxid poisoning in which a record of over 6,500,000 has 
been made. 

3. Changes in Shape and Structure of the Red Corpuscles in 
Disease. — The red corpuscles show great variations in shape in 
the anemias, more particularly in profound secondary anemias 
and in pernicious anemia. Changes in shape are called poikilo- 
cytosis (Fig. 90 and 91); the corpuscles becoming elongated 
or oval, pear-shaped, or with irregular edges. Changes in size 
also occur, very small corpuscles being met with (microcytes), 
and others larger than normal (macrocytes). Vacuolation of 
the corpuscles also occurs; in dried and stained specimens 
the vacuoles appear as clear, unstained, and sharply defined 
round or oval spaces. In fresh blood these vacuoles change 
their shape, and are, no doubt, present in the corpuscles in 



THE RED CORPUSCLES 



301 



the blood. A granular degeneration of the corpuscles is seen 
in some cases. Deformed corpuscles sometimes show irregular 
movements, which are described as ameboid. They do not, 
however, possess the definite characteristics of the ameboid 
movements of the leukocyte. The changes which have been 
described are taken as indicating necrobiosis or degeneration 
of the corpuscles, and no doubt this may be taken as, in the 
main, correct. Whether, however, the degeneration occurs in 




Fig. 90. — Blood in pernicious anemia. 

The drawing shows the characteristic shapes of the red cor- 
puscles in advanced pernicious anemia. Some are pear-shaped, 
some oval, and some kidney-shaped — poikilocytosis. Some of the 
corpuscles are large— macrocytes ; others are small— microcytes ; 
some are vacuolated. 

the blood itself, or whether it takes place in the red marrow, 
is not known. Another change which may be described as 
a form of degeneration is an irregularity in the staining 
properties of the corpuscle. Thus, the red corpuscles normally 
have an affinity for acid stains, such as eosin and aurantia. 
By the Ehrlich-Biondi stain, which contains orange G, acid 
fuchsin, and methyl green, the corpuscles are normally stained 
dark lemon color, and the nuclei greenish. The diseased 
corpuscles will take up the methyl green, as well as the 



3° 2 



CHANGES IN THE BLOOD IN DISEASE 



orange, giving a reddish-purple result. Such cells, which are 
nearly always deformed, are referred to as polychromatophilic. 
Nucleated red corpuscles (Fig. 92) are normally absent 
from the blood, although they are present in the bone marrow. 
They occur in the blood in many cases of disease, and are 
of various forms. The normoblast is precisely similar to the 
erythroblast of the bone marrow. It is an immature red 




Fig. 91. — A blood film in splenic anemia. 

This figure represents the varying shape and size of the red corpuscles 
in the blood in splenic anemia. The tendency to the oval form of the red 
corpuscle is well shown. One nucleated red is seen, and the leukocytes are 
few in number. 

corpuscle which has entered the blood stream before its time. 
The nucleus is frequently irregularly situated, as, indeed, it 
is in the erythroblast. It may be central or peripheral, or 
even projecting from the surface. The term microblast is 
given to the small nucleated red corpuscle; the term megalo- 
blast to the nucleated red corpuscle larger than normal. The 
megaloblast is a degenerated cell with a very large nucleus, 
surrounded by a pale corpuscular body. The cell shows 
an irregular staining and is polychromatophilic. Irregular 



THE RED CORPUSCLES 303 

nucleated red corpuscles are not infrequently observed in pro- 
found anemias. Thus, a very small degenerate nucleus may 
be seen in a large cell. The nucleus may show karyokinesis, 
and the bifid nucleus may also undergo degeneration. Dif- 
ferent significance has been given to the presence of the va- 
rieties of nucleated cells in the blood, the megaloblast, for ex- 
ample, being considered as of the most serious import. It may 
be said, however, that the normoblast is practically an unde- 
generated erythroblast, and the microblast is an immature 
erythroblast, and that the megaloblasts are erythroblasts show- 
ing more or less extensive degeneration in the nucleus, as well 
as in the body of the corpuscle. In so far, therefore, as the 
megaloblast shows more advanced degeneration, its import is 
more serious than that of the normoblast. 



1 



« 



#* 



Fig. 92. — Nucleated red corpuscles. 



The figure shows the varying shape of nucleated red corpuscles (normoblasts, 
microblasts, megaloblasts) which are seen in the blood in pernicious anemia, leu- 
kemia, cases of advanced secondary anemia. 

The Condition of the Blood in Anemia. — The condition of 
anemia or bloodlessness is usually divided into two classes, 
primary and secondary. To the first belong chlorosis and 
pernicious anemia; to the second belong those anemias which 
follow, or are associated with, some disease, toxemia, or dis- 
ordered nutrition. It is, however, probable that no anemia is 
really primary; that, for example, the profound destruction of 
red corpuscles which occurs in pernicious anemia is secondary 
to some toxic or other condition, which profoundly interferes 
with blood formation or directly destroys the corpuscles in the 
blood. There is indeed strong evidence that many cases of 
pernicious anemia are associated with, if not directly due 
to, a process of intoxication, more particularly from bacterial 
growth in the mouth and the intestinal tract. Chlorosis is 
secondary to some defective formation of the body, or some 
irregularity in the uterine functions, aided by external non- 
hygienic conditions. No accurate explanation is, however, 



3 o 4 CHANGES IN THE BLOOD IN DISEASE 

forthcoming of the causation of the blood change in chlorosis. 
It is a disease of young females under the age of twenty-four 
years, and most commonly arises at or near puberty. In many 
instances it runs in families. The blood condition does not 
show destructive changes, as in pernicious anemia. Splenic 
anemia is a name given to certain anemic conditions occur- 
ring more particularly in children, in which, in addition to 
the blood changes, the spleen is enlarged. The blood changes 
may at one time be of the chlorotic type, and later, of the per- 
nicious anemia type. As in the other severe anemias, there 
are periods of pyrexia during the course of the disease. A 
secondary or symptomatic anemia may be associated with very 
different conditions, and may be of varying degrees. Four 
degrees of secondary anemia have been described (Cabot). 

First Degree. — In this there is a diminished amount of 
hemoglobin, and a lowered specific gravity of the blood, 
without any diminution in the number of corpuscles. 

Second Degree. — There is a diminished amount of hemo- 
globin, but no appreciable diminution in the number of red 
cells, which show, however, some degenerative changes. Thus 
rouleaux formation is lost, and the cells vary in size, 
microcytes and macrocytes being present, while poikilocytes are 
observed, as well as vacuolation and irregular staining with 
the Ehrlich triple stain. 

Third Degree. — There is a diminution in the amount of 
hemoglobin, and in the number of corpuscles; and, in addition, 
normoblasts may be observed. 

Fourth Degree. — In addition to the changes seen in the 
third degree, microblasts and megaloblasts are present, the 
latter more commonly than the former. 

The conditions associated with secondary anemia are very 
various, and are such as infective disease, malignant disease, 
chronic suppuration, chronic dysentery, renal disease, cirrhosis 
of the liver, bad hygienic conditions, rapid child-bearing and 
prolonged lactation, intestinal parasites, and poisons, such as 
lead and arsenic. 

The First Degree of Secondary Anemia may be observed in 



SECONDARY ANEMIA 305 

such conditions as bad hygienic surroundings, multiple preg- 
nancies, prolonged lactation, and following some infective 
diseases. 

The Second Degree is more common than the first, and is 
observed in cases of malignant disease, cirrhosis of the liver, 
leukemia, lead-poisoning, and in such infective conditions as 
typhoid fever, erysipelas, tuberculosis, pyemia, measles, and 
scarlet fever. The changes in the blood in these conditions 
may resemble those present in some cases of pernicious anemia. 
Frequently, however, the necrobiotic changes are not so marked 
as in the latter condition. 

The Third Degree of anemia, frequently without the pres- 
ence of normoblasts, is observed in the anemias of infancy and 
early childhood; soon after the occurrence of large hemor- 
rhages, in malaria, and in acute septicemia. 

It is evident that the causes which may, in these condi- 
tions, be supposed to affect the structure of the blood are 
various. 

1. Thus, in some there is the presence in the body of 
poisonous substances which, by their long-continued action, 
may exercise a profound effect on blood formation and on 
the vitality of the red corpuscle. This would occur in infective 
disease, including chronic suppuration and chronic dysentery. 
The action of lead and arsenic in producing changes in the 
blood may be ascribed to the same cause, that is, a chronic 
toxic condition. 

2. In other conditions there is actual loss or destruction of 
the red corpuscles. Such loss occurs after large hemorrhages. 
Obvious and great destruction occurs in malaria, more par- 
ticularly the chronic form. 

3. The main cause in the production of some forms of 
secondary anemia must be ascribed to the interference with 
the functions of an important organ, or with the assimilation 
of food. This would occur in cirrhosis of the liver, in renal 
disease, and in malignant disease of an important organ. 

Primary Anemia: Chlorosis, Pernicious Anemia. — The best 
examples of primary anemia are chlorosis and pernicious 



306 



CHANGES IN THE BLOOD IN DISEASE 



anemia, but although they may provisionally be classed 
together as primary, the blood changes are in great contrast. 

In chlorosis (Fig. 93), the blood, when drawn, is pale and 
watery, coagulating readily. The specific gravity is 1030, or 
slightly more. The red cells average a little over 4,000,000 
to the cubic millimeter; it is not common to find them much 




Fig. 93. — Blood in chlorosis. 

The figure shows a film of the blood corpuscles in chlorosis. Many of 
the red corpuscles are normal in shape, but a few are oval, and some are 
pear-shaped. Some are smaller than normal, but there are no macrocytes. 



below 2,000,000. The hemoglobin averages 41 per cent., while 
the color index is low — on an average about 0.5. The red 
cells are pale, and somewhat diminished in size. Macrocytes 
are very rare, while microcytes are fairly common; poikilocy- 
tosis is frequently observed to a slight degree, but it is very 
rarely well-marked. The presence of nucleated corpuscles has 
been observed, but their occurrence is extremely rare. Leuko- 
cytosis is, as a rule, absent, though an increase of the lympho- 



PERNICIOUS ANEMIA 307 

cytes may be present. Myelocytes are very rarely observed, 
and the blood plates are increased. 

In pernicious anemia (Fig. 88) the blood, when drawn, is 
pale and watery; it is very fluid, and very slow in coagulating". 
The red corpuscles show no rouleaux formation; their average 
number per cubic millimeter, when the individual first comes 
under medical observation, is a little over 1 ,000,000 ( 1 ,200,000) . 
In the later stages the number drops to 500,000, and may even 
be as low as 143,000 (Quincke). The hemoglobin varies from 
18 to 40 per cent., the average being about 35 per cent. The 
color index is usually over 1. Microscopically, the red cells 
show great variations in size (macrocytes and microcytes), as 
well as in shape (marked poikilocytosis). Polychromatophilic 
cells are frequently met with, as well as nucleated red cells, 
megaloblasts being more common than normoblasts. The white 
corpuscles are diminished, even to 500 per cubic millimeter. 

The contrast between the blood in chlorosis and that in 
pernicious anemia is therefore well marked. In the former 
the chief change is in the diminution in the amount of hemo- 
globin, and to this diminution is to be ascribed the low specific 
gravity of the blood. The specific gravity of the plasma is not 
diminished, and may be increased. The change in shape of 
the corpuscles is but slight, and there is no diminution in the 
number of leukocytes. There is in chlorosis, therefore, no 
evidence of blood destruction, which is the main feature of 
the blood in pernicious anemia. The great diminution in 
the number of corpuscles in this disease, with their marked 
degeneration, shows that they are the chief element affected. 
The plasma and white corpuscles are also affected, as shown 
by the diminished coagulability of the blood, and the diminu- 
tion in the number of leukocytes. 

The tissue changes which occur in profound anemias are — 
(1) a deposit of hemosiderin in the liver or spleen (Chapter 
XIV.), or pigmentation; (2) fatty changes in the heart, liver, 
and kidneys (p. 203); (3) hemorrhages (Chapter XIV.); 
(4) changes in metabolism (Chapter XVIII. ), and in the cen- 
tral system (Chapter XIX.). 

2. The White Corpuscles (Leukocytes) : Blood Platelets. — 



3 o8 



CHANGES IN THE BLOOD IN DISEASE 



The average number of leukocytes per cubic millimeter is about 
7500, but this number varies considerably, not only in different 
individuals, but in different conditions of the same individual. 
The number of blood plates has been reckoned to be between 
200,000 and 300,000 per cubic millimeter. The following" are 
the varieties of leukocytes normally present in the blood 
(Fig. 94) : 

The Lymphocyte is a small cell of an average diameter of 



m m # 

1 f<* « 





Fig. 94. — Varieties of leukocytes (as stained by eosin and 
methylene blue). 

1 and ia. The lymphocyte is a small cell with a large nucleus and 
but little protoplasm, which does not contain granules staining red with 
eosin. 

2 and 7.a. The mononuclear leukocyte (macrophagocyte) is larger 
than the lymphocyte, while it contains more protoplasm. No granules 
staining red with eosin. 

3 and 3#. The polymorphonuclear leukocyte (microphage) is charac- 
terized by a multilobed nucleus, surrounded by protoplasm, which con- 
tains numerous fine granules staining red with eosin. 

4. The eosinophile leukocyte has a multilobed nucleus, and is char- 
acterized by the large granules, which stain red with eosin. 

5 and 5a. The myelocyte has a large oval nucleus staining poorly 
with methylene blue, and the protoplasm also does not stain well, and 
has fine granules staining red with eosin. 

6. The eosinophile myelocyte is like the myelocyte, but has large 
eosinophile granules, like the eosinophile leukocyte. 

10 ju, and has a round nucleus, staining deeply with aniline 
dyes, and a small amount of protoplasm, which stains lightly. 
It forms from 20 to 30 per cent, of the leukocytes of human 
blood, is increased in number after food, and closely resembles 
the small cells of lymphoid tissue. In children the percentage 
of lymphocytes may be from 40 to 60. It is not ameboid, and 
does not act as a phagocyte. 

The Large Mononuclear Leukocyte forms 4 to 8 per cent, of 
the leukocytes, and is of an average diameter of 13 ju (p. 32). 

Polymorphonuclear Neutrophile Leukocyte forms 62 to 70 



THE LEUKOCYTES 309 

per cent, of the leukocytes, and is of an average diameter of 

13-5 * (p. 32). 

The Eosinophile Leukocyte, or coarsely granular oxyphile, 
forms only a small proportion of the leukocytes of the blood 
(1-2 to 4 per cent.), and is of an average diameter of 12 p.. 
It is found abundantly, like the next form, in celomic fluid, 
in serous cavities, connective tissue, and in bone marrow. 
Unlike the hyaline cell, its protoplasm, which is abundant, 
contains relatively large granules which stain with acid dyes, 
such as eosin, and not with alkaline dyes, such as methylene 
blue and basic fuchsin.* The nucleus is lobed like that of the 
preceding form. The eosinophile leukocyte is ameboid, and 
is non-phagocytic. Two other forms of leukocytes, neither of 
which is phagocytic, but both of which are basophile cells, are 
described. 

Coarsely Granular Basophile Leukocytes are present in 
celomic fluid, but are absent from human blood in health. They 
are present in leukemia. They have a round nucleus, and the 
granules of the protoplasm, which are large, stain with basic 
dyes. 

Finely Granular Basophile Leukocytes (mast cells) are very 
small cells, with a trilobe nucleus, the protoplasm containing 
very small granules staining with basic dyes. They form 
1-40 to 1-2 per cent, of the leukocytes, and are increased after 
meals. 

In disease, other forms of leukocytes make their appearance 
in the blood. These are> The Myelocytes, or mononuclear 
cells, with neutrophile granulation; the Eosinophile Myelocyte, 
or mononuclear eosinophile cells, and the small Neutrophile 
Pseudo-Lymphocytes. 

1. The Myelocyte is a large cell, 15.75 " m diameter, with a 
large oval or reniform nucleus, staining faintly, and situated 

*The term acid and basic dyes does not necessarily mean that the 
substances are acid or alkaline to test paper, the dyes being a compound 
of acid and base used in their technical senses. In the acid dyes there 
is an excess of the acid moiety ; in the basic dyes an excess of the basic. 
Eosin is thus an acid dye, methylene blue a basic. Ehrlich's " neutral " 
stain acts really as an acid dye. 



3 io CHANGES IN THE BLOOD IN DISEASE 

either centrally or at the periphery of the cell. The proto- 
plasm shows neutrophile granulation, thus differing from the 
large mononuclear cells. The myelocytes vary in size; and, 
unlike the polymorphonuclear neutrophile leukocyte, they show 
no ameboid movement. In disease, the myelocytes are found 
mainly in splenic myelogenous leukemia, but they have also 
been found in sarcoma of the bone marrow; in severe post- 
hemorrhagic anemia; in severe mercurial poisoning; in anemia 
pseudo-leukemica infantum, and in some infective diseases, 
such as diphtheria. 

2. The Eosinophile Myelocyte shows the large oxyphile 
granulations characteristic of the eosinophile cell, and is found 
mainly in splenic myelogenous leukemia and in anemia pseudo- 
leukemica infantum. 

3. The Neutrophile Pseudo-Lymphocytes are about the same 
size as the lymphocytes, but show neutrophile granulation of 
the protoplasm. They have been found in hemorrhagic small- 
pox and in recent pleuritic effusion, but their exact significance 
or origin is unknown. 

'Alterations in the Number and Character of the Leukocytes 
in Disease. — The number of leukocytes may be diminished — a 
condition called leukopenia — or they may be increased in 
number. The increase may be one affecting only the normal 
leukocytes of the blood — a condition called leukocytosis; or 
one particular variety of normal leukocyte may be increased — 
as when the lymphocytes are increased, lymphocytosis, or the 
eosinophile cells are increased, eosinophilia. On the other 
hand, there may be a large addition made to the number of 
leukocytes in the blood by the presence of myelocytes, as in 
splenic myelogenous leukemia, and a very large increase of 
lymphocytes, which occurs in lymphatic leukemia, as dis- 
tinguished from the moderate increase which occurs in 
lymphocytosis. 

By some, two classes of leukocytosis are made : Active Leuko- 
cytosis, in which the leukocytes which are increased are those 
showing ameboid movement; namely, the polymorphonuclear 
neutrophile, the eosinophile, and the mononuclear leukocytes; 



LEUKOCYTOSIS 3TI 

and Passive Leukocytosis, in which the increase is of non- 
ameboid leukocytes, such as the lymphocyte and the 
myelocyte (Ehrlich and Lazarus). This classification is a 
useful one, as it contrasts the kinds of leukocytes which are 
increased. 

Active Leukocytosis. — This is divided into (a) Polymorpho- 
nuclear Leukocytosis, with the subdivisions: (I.) Polymorpho- 
nuclear neutrophile leukocytosis; and (II.) Polymorphonuclear 
eosinophile leukocytosis; and (b) Mixed leukocytosis, in which, 
in addition to the above, the mononuclear elements are affected. 

1. Polymorphonuclear Neutrophile Leukocytosis is the ordi- 
nary form of leukocytosis. These leukocytes are not derived 
from the lymph glands, as Virchow supposed, but by an emi- 
gration from the bone marrow (Ehrlich). The eosinophile 
cells are diminished, sometimes considerably. This form of 
leukocytosis occurs both in physiological and pathological 
conditions. 

i. Physiological Leukocytosis is observed: 

(a) In the newly born, in which, up to the fourth day, the 
leukocyte count may be as high as from 17,000 to 30,000 per 
cubic millimeter. 

(b) During digestion. — Starvation greatly diminishes the 
number of leukocytes, sometimes to 1000 per cubic millimeter. 
In one to five hours after a meal, rich in proteids, leukocytosis 
is observed, the increase being sometimes 33 per cent. The 
change is more marked in children than in adults. 

(c) In pregnancy, in the later months, there is leukocytosis, 
which may be as high as 13,000 per cubic millimeter. This is 
more marked in primiparse. The leukocytes are also increased 
after parturition. 

(d) Bodily exercise and cold baths also increase the leuko- 
cyte count. 

2. Pathological Leukocytosis, 

(a) In acute and chronic anemic conditions, leukocytosis 
occurs, especially after profuse or long-continued hemorrhages. 

(b) Inflammatory leukocytosis (Fig. 95) is the most fre- 



3 i2 CHANGES IN THE BLOOD IN DISEASE 

quent form of polymorphonuclear neutrophile leukocytosis. It 
occurs in infective diseases, during their continuance; such as 
in local infections or abscesses, in septicemia, pneumonia, ery- 
sipelas, diphtheria, and scarlet fever; while in typhoid fever, 




Fig. 95. — Blood film in leukocytosis. 

The figure shows the large increase in the blood of the polymorphonuclear leuko- 
cyte—inflammatory or infective leukocytosis. The blood platelets are also greatly 
increased. The red corpuscles are normal. From a case of mouth infection ending 
in gangrene. 

measles, malaria, influenza, rotheln, mumps, cystitis, and tuber- 
culosis, polymorphonuclear leukocytosis is absent. In typhoid 
fever and measles there may be leukopenia. 

3. Toxic Leukocytosis occurs in poisoning by illuminating 
gas and quinin; it follows the administration of salicylates and 
is also observed as the result of etherization. It is seen follow- 



LEUKOCYTOSIS 313 

ing injections of tuberculin and thyroid extract. To a toxic 
action may perhaps be ascribed the polymorphonuclear leukocy- 
tosis which occurs in chronic renal disease, in acute yellow 
atrophy of the liver, in some cases of cirrhosis of the liver, and 
in cases of gout. 

A large number of substances have been tested as regards 
their effect in producing an increase of leukocytes. Thus, the 
administration of camphor and some of the essential oils by the 
mouth causes an increase of leukocytes; the subcutaneous injec- 
tion of albumoses, pepsin, nuclein, extract of leech and curare 
lead to the same result; while, in the case of irritants subcu- 
taneously injected, such as turpentine, croton oil, and salts of 
mercury, great leukocytosis was produced, which appeared to 
be out of proportion to the amount of local reaction produced. 
The action of bacterial poisons in producing polymorphonuclear 
leukocytosis is partly considered with the subjects of Phagocy- 
tosis and Chemiotaxis (p. 27). From experiments which 
have been performed it appears that the degree of leukocytosis 
depends on the age of the animal and the dose of the poison, 
and on the resistance or degree of immunity of the animal. 
Thus, young animals show greater leukocytosis than older ones. 
A very large dose of toxin causes a reduction in the number of 
leukocytes, and a non-fatal dose produces leukocytosis ; a slowly 
fatal dose causes a varying effect; while in immune animals, 
there is but little, or no, leukocytosis. These results are to be 
explained by the facts which have already been discussed under 
the heading of Immunity (Chapter VI.). Leukocytosis, as the 
result of bacterial poisoning, appears to be dependent on the 
slow action of the poison. This action is absent in immune 
animals; therefore but little leukocytosis results. 

4. Mononuclear Leukocytosis is observed in malignant tumors. 

II. Polymorphonuclear Eosinophilc Leukocytosis. — The 
eosinophile cells are increased in certain diseased conditions — 
sometimes relatively and sometimes absolutely; that is, instead 
of constituting 1-2 to 4 per cent, of all the leukocytes, they may 
form 10. 20, or 30 per cent., or even above this. The average 
normal number of eosinophile cells to the cubic millimeter is 



3 i 4 CHANGES IN THE BLOOD IN DISEASE 

between ioo and 200. This may be increased in disease to 
over 4000, and as many as even 29,000. An increased number 
of the polymorphonuclear eosinophile cells is observed in 
healthy infants, but not in adults. Leukemia is sometimes 
associated with polymorphonuclear eosinophile leukocytosis, 
but the conditions in which it has been more particularly ob- 
served are as follows : 

(a) In bronchial asthma an increase has been observed up 
to 10 or 20 per cent. In the sputum of infants and adults 
suffering from the disease eosinophile cells are found, in addi- 
tion to Charcot-Leyden crystals. The leukocytosis is well 
marked at the time of the attacks, and is directly connected 
with the attacks. 

(b) In certain skin diseases eosinophilia is observed, more 
particularly in pemphigus, prurigo, and psoriasis, and the 
degree of leukocytosis appears to be connected with the extent 
of skin involved. 

(c) In helminthiasis. — Eosinophilia has been observed in 
ankylostomiasis more particularly, but also in other cases of 
parasitism of the intestine, as in oxyuris, ascaris, and tenia 
mediocanellata, and in trichiniasis. 

(d) Eosinophilia is also observed during convalescence 
from certain infective diseases; for example, pneumonia, 
rheumatism, and malaria; and has occurred as the result of 
the injections of tuberculin. 

(e) A slight increase in the eosinophile cells has been 
observed in the cachexia associated with malignant tumors. 

Passive Leukocytosis. — 1. Lymphocytosis is a relative in- 
crease in the lymphocytes of the blood. There may, or may 
not, be an actual increase of the total leukocytes, and, with an 
increase of the total leukocytes, the appearances of the blood 
are similar to those of lymphatic leukemia. Relative 
lymphocytosis is observed in the blood of the healthy infant, 
as well as in some diseases of infancy, such as the various 
forms of gastro-intestinal disturbance and infection. Other 
causes are congenital syphilis and scurvy. In adults, it is 
observed in chlorosis, pernicious anemia, and the secondary 



LEUKEMIA 315 

anemia of syphilis; as well as, somewhat irregularly, in 
certain infective diseases, such as typhoid fever, tuberculosis, 
smallpox, and chronic malaria. Usually it is observed towards 
the end of an infective disorder. Absolute lymphocytosis is 
a rare condition. 

II. Leukemia. — Leukemia may be divided into two groups 
of cases : 

1. Myelocytemia, or splenic myelogenous leukemia, in which 
there is an enlarged spleen, with changes in the bone marrow, 
"but not in the lymphoid tissues generally. The disease runs 
a chronic course, lasting from two to five years. 

2. Lymphemia, or lymphatic leukemia, which exists both 
m the acute and chronic form. The acute lasts six or seven 
weeks, and the chronic from two to four years or more. In 
this disease the lymphatic glands are enlarged, and the spleen 
may also be greatly enlarged. 

1. Splenic Myelogenous Leukemia (Fig. 96). — The blood, 
wnen shed, is opaque and flows sluggishly; coagulation is slow. 
The red corpuscles, in the early stage, show no diminution in 
number, or in the amount of hemoglobin. In the advanced 
disease, the average number of red cells is about 3,000,000 
per cubic millimeter, and the color index averages about 0.6. 
There is poikilocytosis to a greater or less extent, but the 
most characteristic microscopic feature of the red corpuscles is 
the presence of very numerous nucleated red cells, which are 
as numerous as in the worst forms of pernicious anemia. 
The- nucleated cells are usually normoblasts, megaloblasts 
being somewhat uncommon. The white corpuscles show the 
main change in the blood. The number of white corpuscles 
is enormously increased, and the average proportion of the 
white cells to the red is about one to seven, the figures 
varying in individual cases. The highest is one white to two 
red, and the lowest is one white to thirty-seven red; some 
cases are, however, recorded in which the white equal or even 
exceed the red in number. The average number of leukocytes 
per cubic millimeter is about 450,000, while the variations in 



3 i6 CHANGES IN THE BLOOD IN DISEASE 

individual cases are between 98,000 and over 1,000,000. The 
characteristic feature of the blood condition and of the disease 
is the presence of a large number of myelocytes (mononuclear 
neutrophile cells). The presence of these characteristic cells 




Fig. 96. — Blood film in leukemia. 

There is an enormous number of myelocytes (see Fig. 94) in the blood : absolutely 
and relatively to the normal leukocytes. A few polymorphonuclear and mononuclear 
leukocytes are seen, as well as lymphocytes. A few red corpuscles are nucleated 
(normoblasts.) 

gives a picture in the blood preparation in marked contrast to 
that present in leukocytosis. The myelocytes form an average 
of 30 per cent, of the total leukocytes in splenic myelogenous 
leukemia; but their actual number per cubic millimeter varies 
enormously, being from 50,000 to 150,000. The last figure may 
be taken as representing the usual number in the later stages of 



LEUKEMIA 317 

the disease. The eosinophile myelocyte, or mononuclear eosino- 
phil cell, is present in leukemia, but not in such large numbers 
as the myelocyte. Of the normal leukocytes of the blood, 
the eosinophile cells are absolutely increased. The average 
normal number of eosinophile cells per cubic millimeter is 
between 100 and 200. In splenic myelogenous leukemia the 
number is very greatly increased, sometimes to as much as 
fifty or more times than the normal; and this increase con- 
tinues with the progressive increase of leukocytes during the 
course of the disease. In some cases of leukemia the 
eosinophile cells are diminished, and this is observed 
when infection occurs. From numerous observations, it 
appears that absolute increase of the eosinophile cells is an 
integral part of the changes in the blood in splenic myelo- 
genous leukemia. The polymorphonuclear neutrophile cells 
are absolutely increased in comparison with the normal blood, 
but relatively diminished in proportion to the other leukocytes 
present. When the leukemic individual, however, suffers from 
an infective febrile disease, the polymorphonuclear neutrophile 
cells show an enormous increase, and may largely prepon- 
derate over the other leukocytes. This means that, as the 
result of infection, polymorphonuclear neutrophile leukocytosis 
is added to the typical changes of the blood in leukemia. The 
lymphocytes are affected in the same way, but are relatively 
diminished. Coarsely granular basophile cells may be ob- 
served. The finely granular basophile leukocytes are abso- 
lutely increased, and the increase may be considerable. Irregu- 
lar forms of leukocytes are not unfrequently observed, those 
smaller in size than normal, or cells with the nucleus under- 
going division. 

During the remissions which sometimes occur in the disease, 
the spleen is diminished in size and the total number of leuko- 
cytes is decreased. The proportion of myelocytes remains, 
however, about the same. 

2. Lymphemia, or lymphatic leukemia (Fig. 97). — The red 
corpuscles in this condition present much the same appear- 
ances as in splenic myelogenous leukemia, with the exception 
that normoblasts are rather less common. The white cells 



3 i8 CHANGES IN THE BLOOD IN DISEASE 

show an increase, the proportion of white to red being, on an 
average, about two to fifty, the average number per cubic 
millimeter being about 100,000. The great increase in the 
white corpuscles is due solely to the increase in the lympho- 




Fig. 97. — Blood film in lymphemia. 

There is an enormous increase in the number of lymphocytes, which almost com- 
pletely fill the field. There are no myelocytes, and the polymorphonuclear leukocytes 
are not increased. From a case of acute lymphemia (lymphatic leukemia). 



cytes — small and large — which may form 90 per cent, or more 
of the leukocytes present. The lymphocytes often show 
degeneration. The other leukocytes of the blood are dimin- 
ished — both the polymorphonuclear neutrophile and the eosino- 
phile cells; myelocytes are rarely found. In acute leukemia 
the large lymphocytes predominate, and there is great diminu- 



ORIGIN OF THE LEUKOCYTES 319 

tion in the number of the red corpuscles. The blood condition 
in lymphemia is affected, as in splenic myelogenous leukemia, 
by intercurrent disease. In one case septicemia, complicating 
lymphatic leukemia, caused a great increase in the white cells, 
due to polymorphonuclear leukocytosis. In the majority of ob- 
served cases, however, intercurrent disease, such as carcinoma, 
tuberculosis, pneumonia, influenza, erysipelas, and abscess of 
the kidney, decreases the number of leukocytes. The con- 
dition of the blood in lymphemia may be contrasted with that 
in Hodgkin's disease or lymphadenoma. In this disease the 
blood count may be normal, or there may be a moderate degree 
of anemia : and an increase of the leukocytes, when present, is 
due to polymorphonuclear neutrophile leukocytosis. 

Origin of the White Corpuscles. — The place of origin of 
the different forms of leukocyte is of importance in disease. 
The subject has given rise to much controversy, but the main 
facts in relation to it are as follows : There are three places 
of origin : the lymphatic glands and lymphoid tissue throughout 
the body, the bone marrow, and the spleen. 

Production of Leukocytes in the Spleen. — After removal of 
the spleen a general enlargement of the lymphatic glands of 
the body occurs, with occasional changes in the thyroid. Ex- 
perimenting in animals — for example, the guinea-pig — removal 
of the spleen is followed by enlargement of the lymph glands 
during the first year, and this enlargement is accompanied by 
an increase in the number of lymphocytes in the blood, or 
lymphocytosis. In a longer period after splenectomy, there is, 
in the guinea-pig, a great increase of the eosinophile cells. At 
no time are the cells which correspond to the polymorphonuclear 
neutrophile leukocytes of man increased. Cases of splenectomy 
in man have not been examined, as regards the blood condition, 
with sufficient persistence to allow any correct deductions to 
be drawn; but, at any rate in some cases, splenectomy is 
followed by lymphocytosis, and this again by eosinophilia. 
The lymphocytosis which is observed is to be ascribed to an 
increased activity on the part of the lymphoid tissue in the 



3 2o CHANGES IN THE BLOOD IN DISEASE 

body; and, on the hypothesis that the eosinophile cells are 
formed in the bone marrow (Ehrjich), the subsequent eosin- 
ophilia is to be ascribed to the increased activity of the bone 
marrow. It must be admitted, however, that the function of the 
spleen in the production of the leukocytes of the blood must be 
very slight, and it is chiefly concerned with producing changes 
in the dying red and white corpuscles in the blood stream. 

Production of Leukocytes in the Lymphoid Tissue. — The 
lymphocytes of the blood are the same cells as those which 
are found in the lymphatic glands and in the lymphoid tissue 
which exists in many parts of the body; for example, in the 
gastro-intestinal tract, in the spleen, and in the lungs. The 
lymphocytes, which normally form about 25 per cent, of the 
leukocytes, are diminished in the blood in cases of extensive 
disease causing destruction of the lymph glands; as, for 
example, in cases of lympho-sarcoma, where they have been 
found to be diminished to 0.6 per cent. In the disease called 
malignant lymphoma, which is characterized by a rapid swell- 
ing in the lymph glands, the lymphocytes are increased, 
possibly as the result of irritation of the glands. The other 
conditions, however, in which the lymphocytes are increased, 
do not add much to our knowledge of their origin. Lympho- 
cytes are cells without ameboid movement; they do not pass 
out of the vessel, and so are not found in inflammatory 
effusions. In gastro-intestinal diseases of infants they are 
increased in the blood, presumably coming from the lymphoid 
tissue in the intestinal tract. Whooping-cough is accompanied 
by an increase in the number of lymphocytes, but the cause 
of this is unknown. It is stated that the injection of pilo- 
carpi increases the lymphocytes, but, as a rule, the effect 
of poisons is not to increase the lymphocytes, but to increase 
the polymorphonuclear neutrophile leukocyte, the leukocyte of 
inflammation and infection. Even in cases of disease, such as 
lymphatic leukemia, in which the number of lymphocytes in 
the blood is enormously increased, the leukocyte which exudes 
in inflammatory areas is the polymorphonuclear neutrophile, 
and not the lymphocyte. 



ORIGIN OF THE LEUKOCYTES 321 

Origin of the Leukocytes in the Red Bone Marrow. — Bone 
marrow contains cells, which are shown to have specific gran- 
ules when properly stained (Ehrlich). These granules are 
(1) neutrophils (2) eosinophile, and (3) basophile. Most of 
the cells found in the bone marrow contain granules; a few 
are free from granules, and to these belong the cells in a state 
of division which are there observed. There is but little 
doubt that the most abundant leukocyte in the blood — the 
polymorphonuclear neutrophile leukocyte — originates in the 
red bone marrow. Transitional forms are to be observed, 
from the mononuclear cells to the polymorphonuclear, the latter 
being an advanced stage of the former and the only ones 
found in the blood. A similar process takes place with regard 
to the polymorphonuclear eosinophile leukocytes. The mono- 
nuclear neutrophile cell, which develops into the polymorpho- 
nuclear neutrophile leukocyte, is the myelocyte. It does not 
enter the blood in normal conditions, and, practically, only in 
one disease — splenic myelogenous leukemia. 

The establishment of the fact that the commonest leuko- 
cyte in the blood — the polymorphonuclear neutrophile — has its 
origin in the bone marrow, is very important, inasmuch as 
leukocytosis, or the increase of the total leukocytes of the 
blood, is shown by an increase of this polymorphonuclear 
neutrophile leukocyte, and, indeed, it has been said that leuko- 
cytosis is a function of the red bone marrow (Ehrlich). 

Disease of the red bone marrow has a varying effect on the 
leukocytes of the blood. It is not often that the bone marrow 
is so extensively diseased as to leave no normal marrow to 
continue the functions. In some cases, however, of tumor of 
the bone, the bone marrow is replaced by growth, and a severe 
anemia may result, with a moderate leukocytosis. In other 
cases, however, besides the anemia and the occurrence of 
nucleated red corpuscles, there is a great increase in the 
leukocytes, mainly due to the presence of myelocytes; this, 
however, is a rare condition. In acute lymphemia the bone 
marrow is replaced by lymphoid tissue, and the change is so 
extensive that a great alteration in the leukocytes of the blood 
takes place, there being a great diminution in the poly- 



322 CHANGES IN THE BLOOD IN DISEASE 

morphonuclear neutrophile leukocyte. In the marrow itself 
the neutrophile cells are, however, scanty. In some of the 
Mood diseases which have been described, the yellow bone 
marrow becomes red like " currant jelly," and takes on blood- 
forming functions. 



B C 



E "b F 





B C 



f; 



' Hi" 





Fig. 98. BLOOD SPECTRA. 



CHAPTER XII 

changes in the blood in disease — continued 

II. Changes in the Hemoglobin: Hemolysis, Hemoglobinemia 

Hemoglobin, the coloring matter of the blood, is found 
only in the red corpuscles, and not dissolved in the plasma. 
The plasma has its own yellow coloring matter, which is called 
lutein. In the corpuscles hemoglobin exists in the form of 
reduced hemoglobin and oxyhemoglobin. Reduced hemo- 
globin gives a characteristic spectrum of a broad absorption 
band between the lines D and E (Fig. 98). Oxyhemoglobin 
gives two bands, a narrow one close to D and a broader one 
nearer E. Methemoglobin is a derivative of hemoglobin, 
and may be prepared from it artificially by the action of 
oxidizing agents, such as potassium permanganate and nitrite 
of amyl. It is a dark chocolate color, and contains oxygen 
probably in firmer combination than in oxyhemoglobin. It 
may be obtained in a crystalline form, and shows three 
absorption bands in the spectrum, one in the red between C 
and D and two between D and E, differing somewhat from 
the similar lines of oxyhemoglobin. Methemoglobin may 
be transformed into oxyhemoglobin, and then to reduced 
hemoglobin by means of ammonium sulphid or sodium 
hyposulphite. Hematin is a product of decomposition of 
hemoglobin, which is produced by the action of strong 
alkalies or acids. It exists in an alkaline or acid form, and 
combines with hydrochloric acid to form hydrochlorid of 
hematin or crystals of hemin. Both acid and alkaline 
hematin give spectra differing from that of hemoglobin. 

323 



324 CHANGES IN THE BLOOD IN DISEASE 

Hematin contains iron, but has certain derivatives which are 
iron-free. These are chiefly hematoporphyrin and hematoidin. 
Hematoidin is considered elsewhere (Chapter XIV.)- Hema- 
toporphyrin occurs in certain combinations in urine. 

Part of the subject now under consideration concerns the 
presence in the circulating blood of hemoglobin, set free by 
the solution of the red corpuscles. Methemoglobin in these 
conditions may be found in the urine, but has not been 
observed in the circulating blood. The hemoglobin which 
is set free is passed out of the body in the urine, either 
as hemoglobin or methemoglobin. In some instances this 
condition is associated with jaundice (Chapter XV.), but in 
most cases this association is not observed. The solution of 
red corpuscles in the blood is due to many different causes, 
some of which are clear, such as those due to poisons, while 
others are still obscure. Hemoglobin is a cell derivative; that 
is, it is originally formed in cells, and in the healthy body it 
is contained solely within formed elements, the red corpuscles. 
There is, however, more or less continuous destruction of 
certain of the red corpuscles occurring in the liver and spleen, 
and the hemoglobin goes to the formation of the coloring 
matter of the bile. 

With the doubtful exception of the spleen, hemoglobin is 
nowhere in solution in the liquids of the body. When the 
corpuscles are removed from the body, the coloring matter 
is readily dissolved by the addition of distilled water to them, 
and this solution is prevented by the addition of salts to the 
water. The solution of hemoglobin by distilled water, and 
its prevention by the addition of salts, may simply mean that 
distilled water kills the cell, and so dissolves its readily 
soluble contents. The discovery, however, of certain sub- 
stances which, added to the blood outside the body, readily 
dissolve the coloring matter from the corpuscles, or, as it is 
said, produce hemolysis, is an important fact in the explana- 
tion of the solution of the hemoglobin from the red corpuscles 
in disease. These substances are certain bacterial poisons and 
the sera of certain animals, 
. The condition of disease in which the red corpuscles are 



HEMOGLOBINEMIA 3 2 5 

destroyed inside the vessels, producing hemoglobinemia and 
causing the appearance of the coloring matter in the urine, 
hemoglobinuria, are as follows : 

1. Toxic Conditions. — In poisoning by chlorate of potash, 
pyrogallic acid, arseniureted and phosphoreted hydrogen, by 
quinin, and in severe cases of mineral acid poisoning, hemo- 
globinemia and hemoglobinuria are observed. 

Also as the result of the action of snake-venom and certain 
vegetable poisons, such as ricin, abrin, and crotin. 

2. In sunstroke, frost-bite, and severe burns. 

3. As the result of the injection of the blood of one animal 
into another. 

4. In infective disease, such as septicemia, pyemia, typhoid 
fever, and scarlet fever. 

5. In other conditions, of which the cause is unknown, such 
as the conditions referred to as paroxysmal hemoglobinuria, 
Raynaud's disease, and infantile hemoglobinuria. 

After the destruction of the red corpuscles, the coloring 
matter is discharged in the urine, either as hemoglobin or as 
methemoglobin. In both cases it is usually in solution, but it 
may be partly precipitated as a brownish sediment. A few red 
corpuscles may also be observed. In the same case the color- 
ing matter may at one time be discharged as hemoglobin, and 
at another time as methemoglobin, and it is probable that the 
change into methemoglobin takes place in the urine itself. 

1. Toxic Hemoglobinemia. — The occurrence of hemoglob- 
inuria as a sequence of poisoning by chlorate of potassium or 
pyrogallic acid is simply explained by the drug destroying a 
certain number of corpuscles, liberating the hemoglobin, which 
is then discharged in the urine. With its occurrence there is 
an increase in the amount of urea excreted. Quinin is said to 
produce this effect, when given in certain cases of chronic 
malaria. 

2. The cause of the destruction of the red corpuscles in sun- 
stroke, frost-bite, and severe burns is not yet determined. It 
is at present not explained by the mere effect of heat or cold 
on the part of the body affected, although, if this were extensive 



326 CHANGES IN THE BLOOD IN DISEASE 

and led to the destruction of a large number of red corpuscles, 
the occurrence of hemoglobinemia is conceivable. It is possible, 
however, that, in these conditions, an element of infection may- 
be present. With severe burns, indeed, this is usually the case. 

3. Hemolysis, following the injection of the blood of one 
animal into another, has already been mentioned in connection 
with Immunity (p. 190). The results obtained have an im- 
portant bearing on the destruction of the red corpuscles in 
disease. The serum of some animals containing, as it is said, 
a hemolysin, dissolves the blood corpuscles of others. Thus, 
the normal serum of the dog dissolves the red corpuscles of 
the guinea-pig, rabbit, rat, goat, and sheep. The property is 
lost if the serum is warmed to 55°-6o° C, but is restored by 
adding the normal serum of the guinea-pig or other animal: 
It is thus seen that the hemolysin consists of two parts, one 
of which is not sensitive to heat, and the other of which is 
destroyed by heat and exists in the blood of the animal whose 
corpuscles are dissolved. 

The above may be taken as an example of hemolysin 
normally occurring in the blood of an animal. Hemolysins 
may be manufactured by the injection of the blood of one 
animal into another. The serum of normal rabbits has no 
effect on the blood of the ox, that is, it causes no solution of 
red corpuscles; but if rabbits be treated by repeated intra- 
peritoneal injections of ox blood (20-30 c. c.) it is found that, 
after a time, the serum of the rabbit " lakes " fresh ox blood, 
that is, acts as a hemolytic. Thus it is found that as little 
as 0.1 c. c. of the serum will " lake " 2.5 c. c. of a 5 per cent, 
suspension of ox blood in isotonic salt solution. A new body 
has. therefore been formed by the injection in the rabbit of 
the ox blood. This body is called the Immune Body (Fig. 62). 
It requires, for its hemolytic action, another substance or com- 
plement, which exists normally in the guinea-pig's or rabbit's 
blood. The immune body is found resistant to heat and even 
to putrefaction, while the complement is readily destroyed by 
heat. In the sera from different animals the immune body and 
the complement may be obtained, which, in conjunction, will 
cause hemolysis of the blood of another animal. 



HEMOLYSINS 327 

The blood corpuscles of rabbits injected into the horse 
cause the serum of this animal to be poisonous to rabbits, a 
few c. c. being fatal, whereas even 60 c. c. of normal horse 
serum intravenously injected has no serious effect on the rabbit 
(Bellfanti and Corbone). Bordet showed that, in this case, 
there was a specific hemolysin, or immune body, present in the 
serum of the horse, and that this hemolytic property of the 
serum was lost by heating it for half an hour at 55° C, but the 
property was regained by adding normal serum to the warmed 
serum. The following additional examples of this may be 
given : The blood of guinea-pigs, mixed with warmed dog's 
serum (containing immune body), is hemolyzed by fresh 
guinea-pigs' blood serum (containing complement) ; guinea- 
pigs' blood with warmed calf serum is hemolyzed by guinea-pig 
serum; sheep's blood with warmed rabbit serum added is dis- 
solved by calf serum; goat's blood with warmed rabbit serum 
is dissolved by goat serum; and guinea-pigs' blood with 
warmed sheep serum is dissolved by guinea-pig serum. 

The effect of the injection of the blood of one animal 
into another results not only in the production of hemolysins, 
but of other anti-bodies. Thus, the serum of one animal 
treated by the injection of the blood of another animal yields 
an anti-hematic serum, which may contain three kinds of 
anti-bodies : 

1. Agglutinin, which causes the red corpuscles to adhere 
together; 

2. Hemolysin, which dissolves the coloring matter of the 
red corpuscles; and 

3. Precipitin, which precipitates the proteids of the serum. 
The agglutinin and hemolysin are formed when the red 

corpuscles alone are used for injection; the precipitin when 
the serum alone is so used. 

The substances which are described as hemolysins, and 
the other anti-bodies, belong to the same group as the anti- 
toxic and other similar bodies previously discussed in the 
consideration of Immunity. Their chemical nature is not 
yet understood. They are not, however, chemical salts in 
the ordinary acceptation of the term, but are closely related 



328 CHANGES IN THE BLOOD IN DISEASE 

to the nitrogenous proteid substances concerned in the nutri- 
tion of the cell. 

The agglutinin, which causes the red corpuscles to adhere 
together, is not necessarily associated with the hemolysin. 
Thus, although it is found that guinea-pigs repeatedly injected 
with defibrinated rabbit's blood yield a serum which possesses 
both hemolytic and agglutinating action, yet the latter is not 
destroyed by the exposure to 55 C. for half an hour, as is the 
case with the hemolytic. Moreover, goats treated for a long 
time with the corpuscles of the sheep yield a serum which has a 
hemolytic, but not an agglutinating action. It has been stated 
that the serum from anemic subjects (in chlorosis, secondary 
anemias, and leukemia) possesses, in some instances, an 
agglutinating action on the blood of the patient or of healthy 
persons. The subject, however, requires further investigation. 

The hemolysin, as already stated, consists of two parts 
(Fig. 62), the immune body and the complement, the comple- 
ment being sensitive to heat and external conditions, the 
immune body being more resistant. The substances called 
by Buchner Alexins (cytases, Metchnikoff) are anti-bodies 
existing normally in the blood and tissues, or manufactured 
by the different methods already discussed (p. 178). The 
alexins (complement) are sensitive to heat, losing their prop- 
erties by exposure to a temperature of 55 C. Some experi- 
ments, however, seem to show that the immune body combines 
with the red corpuscles, even in the absence of the comple- 
ment. Thus, goat serum obtained from an animal treated 
during a long period with the blood corpuscles of a sheep, 
has a pure hemolytic action on the sheep's blood. This prop- 
erty is destroyed by heat, but is restored by adding normal 
goat serum. If this heated serum is mixed with sheep's blood, 
no hemolysis occurs. The mixture is then centrifugalized, 
and the sediment of corpuscles removed from the supernatant 
clear liquid. To this liquid more blood corpuscles are added, 
as well as normal goat serum. No hemolysis occurs, showing 
that a part of the hemolysin is separated with the corpuscles. 
If to the separated corpuscles normal goat serum is added, 
hemolysis occurs. By this method it may be considered that 



HEMOLYSINS 329 

the immune body, being united to the red corpuscles, is 
separated from the complement, which is destroyed by heat. 

Similarly, normal goat serum dissolves the blood of the 
guinea-pig and rabbit, the activity being destroyed at 55 C. 
Horse serum, which of itself has no action on guinea-pigs' or 
rabbits' blood, restores the activity of the heated goat serum 
when added to it, and a repetition of the experiment, which 
"has just been described, gives the same results. 

It has already been stated that hemolysins may occur natu- 
rally in the blood, or they may be manufactured by injecting 
one animal with the blood of another species. 

Hemolysins may, however, be divided into two classes, in 
one of which, heterolysiu, a specific hemolysin is produced by 
the injection of the blood of another species of animal; as, for 
example, when rabbits are injected with ox-blood. But 
hemolysins are also produced by the injection of the blood 
of the same species as when goat's blood is injected into 
another goat, this hemolysin acting on the blood of the allied 
animals, but not on the blood of the species used. These 
hemolysins are called Isolysins. When a hemolysin is in- 
jected into a normal animal of the same species from which it 
was obtained, an anti-hemolysin is formed which counteracts 
its effects. 

These observations have opened up a new field in the 
pathology of the blood. They indicate the formation in the 
body of toxic substances, that is, of substances having a 
specific physiological action, which are not produced by an in- 
fective agent, but are the result of a disordered metabolism of 
the cell. 

4. The occurrence of hemoglobinemia and hemoglobinuria 
in infective disease is to be explained by the specific action of 
the bacterial poisons circulating in the blood. The rapid post- 
mortem staining due to the diffusion of the hemoglobin and 
occurring in cases of septicemia is an instance of bacterial 
action. Bacterial hemolysins are formed by several pathogenic 
micro-organisms — e. g., by the streptococcus, the staphylo- 
coccus, B. tetani, B. pyocyaneus, typhoid bacillus, B. dysen- 
teriae, and the micrococcus tetragenus. 



33° 



CHANGES IN THE BLOOD IN DISEASE 



5. The similar changes occurring in paroxysmal hemo- 
globinuria, in Raynaud's disease, and in infantile hemoglobi- 
nuria, are, however, not yet explained. Paroxysmal hemoglo- 
binuria and the similar phenomenon which occurs in some cases 
of Raynaud's disease are observed chiefly in men, and are sup- 
posed to be related to a previous infection by syphilis, malaria, 
or gout. The determination of the attack is, apparently, ex- 
posure to cold. Cold undoubtedly initiates the attack, during 
which there is a rapid diminution in the number of red cor- 
puscles in the blood, and the plasma becomes colored by the es- 
caped hemoglobin. The attack is accompanied by an initial 
fall of temperature, succeeded by a reactionary rise. 

Bearing these facts in mind, it is impossible to avoid 
coming to the conclusion that the condition is really a toxic 
one, which is quite unlike the effects of any ordinary effect 
of exposure to cold, particularly as the condition may be 
brought about in the summer, as well as in the cold weather. 
Observations have been made tending to show that the 
exposure of animals to cold for a certain length of time leads 
to destruction of the red corpuscles and to hemoglobinemia, 
but the experiments are far from conclusive. What toxic 
condition is present in paroxysmal hemoglobinuria it is 
impossible to say. 

Infantile hemoglobinuria occurs soon after birth, and is a 
febrile illness, frequently fatal, the chief symptom of which 
is the presence of hemoglobin and methemoglobin in the 
urine. It is not improbable that this condition is due to an 
infective process. 



CHAPTER XIII 

changes in the blood in disease — continued 

III. Coagulability of the Blood in Disease — Thrombosis — 

Embolism 

i. Chemistry of Coagulation. — The coagulation of the blood 
is due to the formation of fibrin, an insoluble proteid body, 
which slowly shrinks, entangling the red, and to some extent 
the white, corpuscles. The precursor of fibrin, fibrinogen, is 
dissolved in the plasma, and, when acted upon by the fibrin 
ferment {thrombin) , is split into a small quantity of globulin 
and a larger quantity of fibrin. The fibrin ferment originates 
in the white corpuscles and blood platelets. These, when they 
disintegrate, liberate a nucleo-proteid {pro -thrombin), which 
combines with the calcium salts, forming the fibrin ferment or 
thrombin. 

The modern theory of the coagulation of the blood thus 
includes the interaction of three substances, the fibrinogen of 
the plasma, the nucleo-proteid of the white corpuscle, and 
the lime salts. The combination of the two last forms the 
fibrin ferment. Nucleo-proteids are compounds of proteids 
with nuclein, and are found both in the nuclei and protoplasm 
of cells. They are obtained from the various solid organs of 
the body, as well as from the lymph glands and the thymus. 
Some contain iron and are called hematogens. They may be 
extracted from tissues by means of the prolonged action of 
water, and are precipitated from solution by acetic acid; or 
they may be separated by grinding up the organ with sodium 
chlorid. and pouring the sticky mass into distilled water, the 
nucleo-proteid rising to the surface. 

331 



33 2 CHANGES IN THE BLOOD IN DISEASE 

In discussing the coagulation of the blood in disease, the 
important points to remember are that the fibrinogen and 
lime salts are present in the blood plasma, whereas the nucleo- 
proteid is present only in the cell elements, and is liberated by 
the disintegration of the cell. 

2. Intravascular Coagulation — Experimental. — The intra- 
venous injection of Schmidt's fibrin- ferment causes coagula- 
tion or thrombosis in the venae cavse, in the right side of the 
heart, and in the pulmonary artery. Similar results are 
obtained by injecting the extracts of various organs. The 
body on which this intravascular coagulation depends is the 
nucleo-proteid. which was called by Wooldridge " tissue 
fibrinogen." Two phases are observed as the result of the 
injection of solutions of nucleo-proteids; a negative phase, 
when the injection is made slowly or only a small dose is given, 
the negative phase being shown in diminished coagulability, 
that is, in increased fluidity of the blood ; and a positive phase, 
or intravascular clotting, when a large amount of nucleo- 
proteid is injected into the veins. Coagulation first takes 
place in the portal system, then in the general venous system, 
pulmonary artery, and the right side of the heart; and lastly, 
in the general arterial system. Very rarely is thrombosis of 
the pulmonary veins observed. The formation of clot is as- 
sisted by an increase in the quantity of carbon dioxid (CO",) 
in the blood. Albino rabbits are not affected. Similar re- 
sults are obtained by the injection of solutions of nucleo- 
proteid from various sources. The substances called artificial 
colloids produce the same result. These substances, artificially 
prepared, resemble, in some of their physical and chemical 
properties, the proteids, but they are not nucleo-proteids. The 
intravenous injection of the venom of the Australian black 
snake also gives two phases, very small doses producing a per- 
manent negative phase or an increased fluidity of the blood; 
moderate and large doses giving a positive phase, that is, an 
instantaneous intravascular clotting. It is noteworthy that, in 
animals in which intravascular clotting has occurred, the blood 
which is not coagulated remains fluid outside the body; so that 
both positive and negative phases are shown in the same animal. 



COAGULATION AND FLUIDITY 333 

It is legitimate to conclude from the experiments that the 
injection of nucleo-proteid into the blood supplies the substance 
which is necessary for the formation of fibrin, but which is 
not normally present in the plasma. Certain substances, such 
as ether, tannin, arsenic, glycerin, and toluylene-diamin, 
when injected in large doses, cause intravascular clotting. 
This probably results from the setting free of nucleo-proteids 
by the disintegration of the white corpuscles. The disin- 
tegration of the white corpuscles is one of the factors in in- 
travascular clotting in disease. 

3. Diminished Coagulability of the Blood. — The diminished 
coagulability of the blood, as mentioned in the last paragraph, 
is present in the negative phase following the injection of 
nucleo-proteids and other substances; it is also produced by 
the injection of certain bodies, the action of which is unex- 
plained. Thus, the intravenous injection of albumoses, such 
as exist in commercial peptone, and of extract of leech have 
a pronounced effect in this way. After the injection of al- 
bumoses in the dog, in a dose of about 0.3 gram per kilo, 
of body weight, the fluid blood may be removed and centrif- 
ugalized. leaving a clear " peptone " plasma. Although this 
plasma does not for a long time spontaneously coagulate, co- 
agulation may be brought about in it immediately by the ad- 
dition of lymph cells, of nucleo-proteids and of calcium 
chlorid. Dilution with water or sodium chlorid solution, neu- 
tralization with acetic acid, or the passage through the plasma 
of a stream of carbonic acid (C0 2 ), also produces coagula- 
tion in it. The effect on the blood of the injection of the 
albumoses passes off, and a second dose is now found not to 
have any effect in diminishing the coagulability of the blood. 
The dog is therefore immune to the albumoses, and the blood 
of this " peptonized " dog confers immunity on a normal dog. 
This fact brings the subject into line with what has already 
been discussed under "Immunity" (Chapter V.), as the re- 
action of the body against toxic substances. The negative 
phase, resulting from the injection of nucleo-proteids, has 
by some been ascribed to the formation from these substances 
of peptone in the blood; but this is not proved. 



334 CHANGES IN THE BLOOD IN DISEASE 

There is some evidence to show that the lungs and liver 
have an effect on the coagulability of the blood, the lungs 
tending to diminish the coagulability, while the liver tends 
to increase it. Thus, if the blood be allowed to circulate 
through the heart and lungs alone, also if the thoracic aorta 
be occluded, the blood gradually loses its power of coagula- 
tion. The functional activity of the liver appears to be neces- 
sary for the specific action on the blood of albumoses. Thus, 
after forming an Eck's fistula (that is, making a communica- 
tion between the portal vein and the vena cava inferior), and 
removing the liver, the injection of albumoses does not produce 
the characteristic blood change. 

The following synopsis may be given of the conditions in 
which coagulation is prevented or hastened, inside or outside 
the body. 

Coagulation is prevented outside the body by the application 
of cold, and by the addition of neutral salts to the blood — 
more particularly of sodium oxalate, which combines with the 
calcium, and so prevents its taking any part in coagulation. 
Inside the body, it is prevented by the injection of albumoses 
and certain other substances, such as abrin, snake-venom, and 
nucleo-proteid in certain doses : also in certain infective diseases. 

Coagulation is hastened outside the body by the application 
of warmth; by contact of the blood with solid bodies; and 
by the addition of calcium salts. Inside the body, it is 
hastened: (i) when the vessels are healthy; in infective dis- 
eases, and in certain cachetic states, or by the intravascular in- 
jection of the substances which have already been considered, 
such as nucleo-proteid, snake-venom, fibrin ferment, laky blood, 
and foreign particles. (2) In diseased vessels it occurs when 
there is solution of continuity of the endothelium or a roughen- 
ing of the surface, and in dilatation of the vessels from disease. 

Thrombosis 

Thrombosis is the term applied to the formation of a throm- 
bus or clot in the heart or living vessels : artery, vein, capillary, 



THROMBOSIS 335 

or lymphatic. The formation of a clot in the vessels in 
disease is, as a rule, a local phenomenon. It has no relation 
to any increase in the amount of fibrin in the blood — a hypo- 
thetical condition, which was formerly called hyperinosis. It 
is a local condition, which may be obviously associated with 
some disease of the vessel or of the surrounding part, or with 
some altered character of the blood. 

The following conditions may be said to lead to the forma- 
tion of a thrombus, either singly or conjointly: (1) A slowed 
blood stream; (2) the presence of foreign bodies in the 
vessels, such as an embolus; (3) discontinuity of the endo- 
thelium and roughening of the intima from disease; (4) an 
altered character of the blood, leading to disintegration of the 
white corpuscles or to an increase of blood plates, and in 
many cases due to the circulation of toxic substances or 
bacteria. 

The Structure and Development of Thrombi. — Thrombi are 
red, white, or mixed, the red being formed in stagnating 
blood, the white and mixed in the moving blood stream. 
The recent red thrombus is composed of fibrin entangling 
red and white corpuscles. It is noteworthy that, if the end 
of the clot be exposed to the moving blqod stream, it 
becomes covered with a white layer, resembling in structure 
the white thrombus. Thrombi formed in the moving blood 
stream are either white or mixed. Although the white 
thrombus may contain a few red corpuscles, it is mainly 
composed of blood platelets, leukocytes, and fibrin, the leuko- 
cytes being the polymorphonuclear neutrophile cells. The 
granular matter, which is seen in sections of the thrombus, is, 
presumably, composed of disintegration granules of the blood 
platelets : some may be due, however, to the disintegration 
of the white corpuscles. Fibrin is seen in anastomosing 
fibrils, which inclose white corpuscles and a few red. The 
leukocytes are more numerous than are found in post-mortem 
clots. Mixed thrombi are frequently stratified, there being 
layers of white thrombus, separated by fewer layers of red 
thrombus. Tt is probable that the red layers are formed by 
ihe blood forcing its way into the white thrombus, stagnating 



336 



CHANGES IN THE BLOOD IN DISEASE 



and clotting, while the white layers are formed like the 
ordinary white thrombus. Hyaline thrombi are found mainly 
in the capillaries, which are distended with 
a homogeneous slightly yellow substance, 
giving Weigert's fibrin stain. 

There does not appear to be any diffi- 
culty in the explanation of the formation 
of the red thrombus. The blood coagu- 
lates en masse and gives the characteristic 
red clot seen in shed blood. The mode of 
formation of the white thrombus, on the 
other hand, as well as that of the hyaline 
a thrombi, has given rise to a great amount 
of discussion. Occurring, as it does, in the 
-I moving blood stream, there is no coagula- 
~ c tion of the blood en masse, and the initia- 
tion of the clot has been ascribed to the 
blood platelets, or the leukocytes, or to 
both. The older view was that the clot 
was mainly due to the accumulation of 
leukocytes at one spot; their subsequent 
disintegration leading to the formation of 
fibrin, which does not, in a moving blood 

showing 9 ^ e D ffe a c g t ra o™ stream > enta «? le ™^ of the red «*" 

the blood stream of puscles. Subsequent experiments, how- 

wSfof Si anery. 6 eVer > shoWed that the initiati °« ° f the 

(*)isthe red axial stream; white thrombus is due, more particularly, 

(c) the narrow plasma zone; . ... <• 1 1 1 i , 1 , 

at (a) the vessel has been to the accumulation of blood platelets, 

scratched, with h. nccdlo 

Beneath the injury the followed by the accumulation of leukocytes 

vessel wall is contracted, « i 7 , • ,• /-r->« 

the axial stream is dimin- — a process called conglutination (rigs. 

ished in size, and between ., N /-r->i .1 1 o 1 • 11 t \ 

the axial stream and the 99 and ioo) ( JtLberth and Schimmelbusch) . 

vessel wall there is a . . ., ri . . r , . A . 

biood piate thrombus. Afterwards fibrin is formed from the 

Within half an hour of the , 1f1 1,-., 111 

injury the thrombus had plasma round the platelets and leukocytes. 

diminished in size, and in , , ,• 1 1 • ,1 • 1 1 , ,1 

two hours showed only a More particularly is this observed at the 

remnant; while the con- . r ,. 1,1, x 

traction at the site of in- margin of the platelets, in connection 

jury was still visible. (Eb- ... ,1 • ,, ,. , 1.1 ,1 

erth and Schimmeibuscho with this, the question as to whether the 
blood platelets exist in normal blood, has been raised, and 
their origin has been ascribed to the disintegration both of 



THROMBOSIS 33 7 

white and of red corpuscles. The origin of the hyaline thrombi 
of the capillaries is not clear. They have been found in the 
lungs,, in the liver and kidneys, and are a feature of the 
action of the hog cholera bacillus (Welch). Some consider 
the hyaline material to be composed of non-fibrillated fibrin; 
others, again, regard it as formed by the coalescence of red 

f <J c a I 




1 ">. ' fia 








■^j^g^v 


O '"7.^4 







Fig. 100. — Drawing showing the results of moderately severe 
injury to the wall of a vein. 

The transverse section of a dog's jugular vein, through the 
length of the wall of which a thin threadhas been drawn. Excision 
after thirty minutes. 

(a~) Advenitia; (b) media; (c) intima; (d and *) portion of the 
thread used in the experiment; (e) heaped-up mass of blood; (/) 
fibrils of fibrin; (#■) blood plate thrombus. 

The result of the injury to the vessel wall is the formation of a 
clot of blood plates. In this clot scattered leukocytes are seen as 
shown by black dots in the figure. The red corpuscular element of 
the blood is almost solely present near the seat of injur}-. (Eberth 
and Schimmelbusch.) 

corpuscles; while some have even considered it to be derived 
from the leukocytes. 

Changes Occurring in Thrombi. — Small thrombi, especially 
those situated in the vails of veins and arteries, may be 
absorbed, some thickening of the intima being left. The 
absorption of the clot, no doubt, is mainly due to a phagocytic 
action of the leukocytes : either those present in the clot itself, 
or those entering the clot from the blood stream. Complete 



338 CHANGES IN THE BLOOD IN DISEASE 

absorption occurs in some instances, leaving, perhaps, some 
slight fibroid thickening of the vessel wall. The clot may also 
soften at the center, and the blood stream be restored through 
the channel formed; this is called tunneling of the clot. 
Partial absorption of the clot may occur, followed by deposi- 
tion of calcium salts. It is more common in veins than in 
other parts, and is the mode of formation of phleboliths. 
In large clots portions may be softened, even though no 
invasion of micro-organisms has taken place. This occurs 
in some clots in aneurysms, and in those occurring in the 
auricles of the heart. The softening is here ascribed to the 
action of a proteolytic ferment, possibly pepsin, in the clot. 

Organisation of the clot may occur. The mass of fibrin, 
leukocytes, and blood platelets takes no part in the forma- 
tion of the fibrous tissue which constitutes the organized clot. 
The endothelium of the vessel proliferates and invests the 
clot. The clot is invaded by leukocytes in the blood, which 
act as phagocytes, and by the new tissue which starts from 
the wall of the vessel. This new tissue is cellular and is 
composed of round or spherical cells and of elongated cells 
or fibroblasts. These are transformed into connective tissue. 
New vessels are formed in the clot by budding from the 
vasa vasorum ; these become lined by endothelium. Organi- 
zation of the clot may result in complete or partial occlusion 
of the vessel. 

Invasion of the clot by micro-organisms frequently occurs. 
In some cases this leads to no naked-eye change in the clot, 
but, in others, softening of the clot occurs, so that it may be 
completely disintegrated. This more particularly is seen when 
the clot is infected by pus-forming organisms. 

Occurrence of Thrombosis in Disease. — Thrombi are ob- 
served in the heart, arteries, veins, capillaries, and lymphatics, 
most commonly in the heart and veins. 

i. Thrombosis in the Heart. — Thrombi are found in the 
cavities of the heart in cases of stagnation of blood in the 
heart, whether due to valvular disease or to dilatation 
secondary to disease of the muscular substance; and to inter- 



THROMBOSIS IN THE HEART 339 

ference with the circulation through the heart, which occurs 
in lung disease, in arterial disease, and in renal disease. 
Not infrequently after death the right ventricle, and some- 
times the left, is occupied by a partially contracted, non- 
adherent clot, which extends through the auriculo-ventricular 
orifice into the auricle, and so into the veins; this is more 
common on the right side than on the left. The clot is partly 
decolorized, partly red. It has been suggested that it is 
formed during the process of dying, and this may be so in 
some cases. As a rule it must, however, be considered as a 
post-mortem phenomenon. It presents quite a different appear- 
ance to the thrombi which are formed in the heart during 
life. These are situated usually in the auricular appendices, 
and are white and globular and adherent to the columnar 
earner. Similar clots, varying in shape, are also to be found 
adherent to the muscular substance between the columnar 
carneae in the ventricles. Globular clots, unattached to the 
heart wall, and called ball thrombi, have been found loose 
in the left auricle in some cases of mitral stenosis. They 
are not common, and are no doubt detached globular clots. 
Thrombi in the auricles are most frequently met with in 
valvular disease of the heart; more particularly mitral disease, 
but they are also met with in cachectic states (tuberculosis, 
cancer, and anemia) towards the end of life, and are found also 
in certain infective diseases, such as enteric fever, although 
rarely. 

Fibrin is deposited in other cardiac conditions, such as 
cm vegetations of the valves, rheumatic or infective, and over 
patches of atheroma in the aortic or mitral valve, or some- 
times over tumors projecting into the heart. This deposit 
of fibrin is not so much dependent on the stagnation of 
blood in the heart as it is on the roughening of the surface 
of the endocardium. 

2. Thrombosis in the Arteries. — Thrombosis in arteries 
usually occurs round an embolus (p. 345). It is rarely caused 
by pressure on the vessel, and is most commonly associated 
with disease of the arterial wall. This disease is either 
clonic arterial disease, such as arterio-sclerosis, aneurysm, 



340 CHANGES IN THE BLOOD IN DISEASE 

and syphilitic disease, or the arterial disease is acute, as in 
acute infective arteritis. It is probable that cases of throm- 
bosis in arteries rarely, if ever, occur in the absence of 
disease of the wall, and this may be either an irregularity of 
the intima, a general thickening of the vessel causing a diminu- 
tion of the lumen, or an invasion of the vascular wall by micro- 
organisms. The arteries which may be affected are those of 
the brain, coronary arteries of the heart, and the peripheral 
arteries — chiefly of the lower limbs. Arterial thrombosis in the 
brain and heart is usually associated with chronic disease, 
either syphilitic or atheromatous. The same may be said of the 
thrombosis which occurs in the arteries of the leg. In some in- 
stances, however, as when arterial thrombosis occurs in typhoid 
fever, in influenza, and in some other infective diseases, there is 
no chronic arterial disease, and it is not possible in all cases 
to determine that the wall of the artery is invaded by micro- 
organisms. This is, however, sometimes the case, micro- 
organisms being found not only in the clot, but in the vessel 
wall, and they may thus be considered as the determining 
cause of the thrombosis. 

Thrombosis of the pulmonary arterial system is usually 
the result of embolism, but it may occur independently of 
embolism, in cases where there is disease of the lung: either 
chronic as in tuberculosis, or acute as in pneumonia and 
gangrene. 

3. Thrombosis in Veins. — This is the commonest form of 
thrombosis observed in disease. Two classes may be described. 
In one the thrombus begins in the venous radicles, starting 
from a diseased focus, which is usually a focus of infection 
(such as suppuration or ulceration). The thrombus increases 
towards the heart, and may extend as far as the large venous 
trunks, but it rarely reaches the large trunk veins. In the 
second class of cases the thrombus arises in a large venous 
trunk, usually of a limb, and passes towards the heart; in 
this way the venae cavse may become affected. In both 
classes of cases the thrombus may be infective or non-infective. 
Examples of the first class may be quoted in the thrombosis 
starting in the uterine veins after parturition; in the veins 



THROMBOSIS IN VEINS 341 

round the appendix in appendicitis; in the radicles of the 

portal vein, when there is ulceration or some other intestinal 

infection; and in the thrombosis in the pulmonary vein, which 

occurs in some cases of tuberculosis of the lungs. Examples 

of the second class may be quoted in the thrombosis of the 

femoral vein, which occurs in certain infective diseases and in 

cachectic states. In the latter case the clot is usually referred 

to as a marantic thrombus. In the two classes of cases just 

mentioned there may be no obvious disease of the vessel wall, 

although, in some cases, the walls of the vein are invaded by 

micro-organisms and so damaged. This is obviously the case 

in well-marked bacterial phlebitis, and in certain other cases 

of phlebitis which occur in gout. Thrombosis occurs in the 

larger veins, when no obvious disease of the vessel wall has 

been observed — e. g., in the femoral veins — more particularly 

on the left side, in the cerebral sinuses, in the veins of the 

arm, and in the pulmonary and superior mesenteric veins. 

The veins of the upper extremity are much less frequently 

affected than those of the lower : in the proportion, it is 

said, of 1 to 50. Of the infective conditions with which this 

kind of thrombosis is associated, the following are the most 

important : Enteric fever, influenza, septicemia, chronic 

tuberculosis, chronic suppuration, chronic dysentery, and 

syphilis. It is observed in other infective conditions, but not 

so commonly as in those enumerated. A similar thrombosis is 

also met with in certain chronic diseased conditions not 

evidently due to infection, such as cancer, chronic diarrhea, 

dilatation of the stomach, profound anemia, chlorosis, and 

renal disease. 

4. Thrombosis in Capillaries. — Hyaline thrombi found in 
capillaries have previously been mentioned (p. 337). They are 
found chiefly in infective diseases, in the capillaries of the 
lungs, liver, and kidneys. They have been observed in pneu- 
monia and in hemorrhagic infarcts of the lung, and are exten- 
sively produced in experimental infection by the hog cholera 
bacillus (Welch). 



Causes of Thrombosis in Disease. — The formation of fil 



)nn, 



342 CHANGES IN THE BLOOD IN DISEASE 

as has been already stated, is due to the action of the fibrin 
ferment which originates in the white corpuscles and blood 
platelets upon the fibrinogen dissolved in the plasma of the 
blood. It is necessary to consider how far this theory of 
coagulation explains the occurrence of thrombosis in disease. 
It is evident that the liberation of the fibrin ferment is the 
main factor in the formation of fibrin, inasmuch as the 
fibrinogen is always present in the plasma. 

The factors which are considered to lead to thrombosis 
are four in number: (i) A slowed blood stream; (2) the 
presence of a foreign body in the blood current; (3) disease 
of the vessel wall; (4) an altered condition of the blood, due 
to a toxemia. 

1. A mere slowing of the blood stream cannot be con- 
sidered, in the majority of instances, as the sole cause of 
thrombosis. It has, however, an important factor, as is seen 
in its occurrence in the auricular appendices and in the 
frequency of thrombosis in the veins. Complete stagnation 
of the blood stream is not commonly observed, but it may 
be seen where there is pressure on a vein, and this complete 
stagnation would lead to thrombosis. That thrombosis is 
more common in the veins than in the other parts of the 
vascular system is due in part to the slower blood flow. The 
thrombus, indeed, more commonly than not, starts from the 
pockets of the valves, where the blood stream is slowest, and 
the veins, more particularly of the larger trunks, with their 
thin walls and lower blood pressure, are more readily affected 
by the contraction of the muscles, which renders the fasciae 
tense, and by their frequently passing beneath the hard- 
walled arteries. In this way it has been explained why the 
left femoral is more frequently thrombosed than the right, 
since it is a long vein, passing obliquely beneath the right 
common iliac artery, and possibly exposed to pressure by the 
sigmoid flexure. 

In the heart cavities the action of the slowed blood 
stream is obvious. Thus thrombosis most commonly occurs in 
the auricular appendices and in the depressions between the 
columnse carnese. Thrombosis is also more common in the 



CAUSES OF THROMBOSIS 343 

right ventricle than in the left, and usually occurs in either 
cavity when it is dilated., and there is great embarrassment 
of the circulation. 

2. The effect of foreign bodies in producing thrombosis 
is seen most obviously when an embolus lodges in an artery 
or vein. This is practically a foreign body, and round it a 
thrombus is rapidly formed, if the patient lives long enough. 
Similar thrombosis is observed round fragments of tumor, 
the cells of an organ, or parasites which accidentally enter 
the circulation. The thrombosis which occurs in these cases 
is. no doubt, initiated by an attraction of the leukocytes to 
the foreign body, leading to the formation of fibrin. 

3. In the case of damage to the vessel wall the conditions 
of thrombosis cannot be stated in a general manner. It may 
be inferred that, in a normal vessel, the vitality of the endo- 
thelium is an important factor in preventing the coagulation 
of the blood. Disease of the intima of a vessel interferes 
with its vitality, but it does not necessarily lead to thrombosis : 
another factor is important, namely, the slowing or stag- 
nation of the blood stream. Thus, the deposition of fibrin 
is not commonly observed over the raised and circumscribed 
patches of atheroma observed in the aorta, even in cases 
where the patch is calcareous and the endothelium is com- 
pletely destroyed. If, however, the aortic disease leads to 
the formation of an aneurysm, the stagnation of the blood in 
the sac is an additional factor leading to thrombosis. In 
these cases the stratified clot is due to the repeated formation 
of a white thrombosis, the red part of the clot being due to the 
coagulation en masse of the blood which has oozed in between 
the layers of clot (p. 335). 

Thrombosis occurring in the peripheral arteries and veins 
is not so obviously explained. In thrombosis occurring in 
the arteries of the leg and leading to gangrene, such as is 
observed in senile gangrene and in diabetes and certain other 
cases which come under neither of these headings, the disease 
of the arterial wall may be extensive. The lumen is diminished 
irregularly, the artery has lost its elasticity and contractility; 
and this, with a weakly acting heart, and thus a slowed 



344 CHANGES IN THE BLOOD IN DISEASE 

circulation, may be sufficient to lead to thrombosis. In some 
of these cases the venae comites are also diseased, the walls 
being thickened, and this additional embarrassment of the 
circulation is an added factor favoring the thrombosis. It 
is possible, indeed, to consider a very atheromatous small artery 
as foreign a body to the blood as a glass tube. Thrombosis 
in syphilitic arteritis is due, not only to the damage to the 
vessel wall, but to the slowed blood stream through the 
greatly narrowed artery. 

In varices of the leg thrombosis frequently occurs, as also 
in hemorrhoids. Here the factors in producing thrombosis 
are the slowed blood stream and the thickening of the vessel 
wall; and, in addition, mechanical injury, such as blows on the 
leg in varices, or the passage of the motions causing inflamma- 
tory thickening of the venous walls in hemorrhoids. In vari- 
cocele, thrombosis is not so common. 

Another class of injury to the vessel wall must be con- 
sired. In anemias (chlorosis and the profound anemias) 
degeneration of the endothelium has been observed; and 
thrombosis, which may occur in these conditions, has been 
supposed to be associated with this damage to the endo- 
thelium. It is very doubtful, however, whether this damage 
can of itself lead to thrombosis. It is probable, in these 
conditions, that there is an additional factor which is the 
main one, namely, some chemical and structural change in 
the blood. In thrombosis occurring in infective disease the 
vessel wall is in many instances apparently normal. In other 
cases, however, it has been found infiltrated with micro- 
organisms and the clot to be invaded by these, so that some 
are inclined to ascribe such thrombosis to the direct and 
local action of the bacteria on the blood. 

4. An altered character of the blood is no doubt, in many 
instances, an important factor, in conjunction with those 
enumerated, in the production of thrombosis. The main 
alteration which would lead to this result is the liberation of 
fibrin ferment by the disintegration of the white corpuscles 
and of the blood platelets. It is considered by some that 
the blood platelets do not exist in normal blood, but that 



EMBOLISM 345 

they are derived either from the white corpuscles or from 
the red. This point is undecided, yet there is but little 
doubt that they play an important part in the initiation of 
thrombosis. A profound effect on the white corpuscles is 
observed in many infective diseases, either in the way of 
increase of particular kinds, or in their disintegration or 
diminution, but how far this effect initiates the thrombosis in 
such diseases as enteric fever and influenza, it is impossible to 
say. It is, however, clear that toxic substances which disinte- 
grate white corpuscles lead to intravascular coagulation (p.333). 
Increase of blood platelets is observed in some diseases, for 
example, chlorosis, in which thrombosis may occur; but, al- 
though blood platelets are said to be relatively increased in 
chlorosis, in leukemia and in many cases of profound anemia 
in which thrombosis may occur, their number is very variable, 
and thev mav be greatly diminished in many infective diseases 
more commonly associated with thrombosis than the anemias. 
The exact relation of the number of blood platelets to the 
occurrence of thrombosis cannot be at present determined. 
The general trend of opinion and observation is to consider 
the occurrence of thrombosis, when there is no disease of the 
vessel wall and slowing of the blood stream, as due to the 
circulation in the blood of the toxic substance, which causes dis- 
integration of the white corpuscles. 

Embolism 

Emboli are bodies which are either formed in some part 
of the circulatory system, and are carried to another part, or 
enter the circulation from without, as when portions of tumor, 
masses of bacteria, fat. or air, get into the circulating blood. 
Emboli are either infective or non-infective; or, as is some- 
times said, septic or simple. As a rule, emboli are formed 
in the circulatory apparatus, and are derived from the follow- 
ing sources : 

Emboli from the Heart (Fig. 101). — Non-infective emboli 
in the heart are usually derived from thrombi in the auricular 
appendices, sometimes in the ventricles. From the right side 



346 



CHANGES IN THE BLOOD IN DISEASE 



of the heart the emboli are carried to the lungs, and from the 
left side into the systemic circulation; the emboli so derived 




EMBOLUS 



Fig. ioi.— Diagram showing the course of pulmonary (blue) and 
systemic (red) embolism. 

In pulmonary embolism the embolus may come through the inferior 
vena cava or from the right heart itself, and pass into the pulmonary 
artery. If large, it blocks a large branch, as shown in the right lung of 
the figure. If smaller, it produces infarctions varying in size. 

In systemic embolism, in which the embolus comes mainly from the 
left side of the heart, the embolus may lodge in one of the large branches 
of the aorta or pass to the brain. It may lodge in the splenic artery, or, 
if smaller, produce infarctions in the spleen. Infarctions in the kidney 
also occur; as well as in the intestine, from an embolus in one of the 
mesenteric arteries. The liver is not affected, owing to the free anasto- 
mosis of its vessels. 

are usually large. Infective emboli are derived from the vege- 
tations in infective (ulcerative) endocarditis, occurring either 
on the mitral, aortic, or pulmonary valves. Embolism of the 



SOURCES OF EMBOLI 347 

systemic circulation occurs when the valves of the left side are 
affected, and of the lungs when the pulmonary valves are 
affected. Large fragments may be detached in such cases, but 
small emboli are not infrequently detached. 

From the Arteries. — Embolism does not commonly result 
from changes in the arteries. A disintegrated atheromatous 
patch may give rise to a fine embolism in rare cases, or a por- 
tion of clot lying at the mouth of an aneurysm may be detached 
and carried into the circulation, blocking the aorta or a large 
vessel. Septic embolism sometimes arises in the aorta in ulcer- 
ative endocarditis, the emboli being carried along the sys- 
temic circulation. 

From the Veins. — The heart and the veins are the sources of 
the larger emboli. In the veins the emboli are portions of 
thrombus, which are detached either by mechanical injury, 
which occurs in the veins of the leg, or after softening by the 
action of bacteria. The emboli may thus be either infective or 
non-infective. Emboli from the vems are carried to the right 
side of the heart, and not infrequently lodge in the pulmonary 
artery. Small fragments of septic venous emboli are carried 
into the smaller branches and even capillaries of the lungs, 
there lodging; and bacteria may even pass through the capil- 
laries of the lungs from this source. Although emboli from 
the veins usually lodge in the pulmonary artery and lungs, yet 
they may pass to the general arterial system without passing 
through the pulmonary system. This occurs when there is a 
patent foramen ovale, and is called crossed embolism. It is not 
common, but it has been observed, not only in thrombi from the 
veins, but in certain cases of irregular deposition of secondary 
malignant tumors. The term retrograde embolism has been 
applied to the condition when the embolism is found on the 
distal side of the thrombus in a vessel; that is, away from the 
heart. This has been observed both in venous thrombi and in 
tumors, more particularly the latter. It has been ascribed to 
a certain backward pressure of blood from the right side of the 
heart itself, but is more probably associated with some obstruc- 
tion of the flow in the veins or lymphatics, leading to increase 
of pressure on the thrombus or portion of tumor, and so to the 
detachment of the fragment on the distal side. 



348 CHANGES IN THE BLOOD IN DISEASE 

In the majority of instances, however, the emboli follow the 
blood stream. If arising- on the left side of the heart, they 
enter the systemic circulation. When large, they are stopped 
in one of the main branches, sometimes at a bifurcation, a 
portion of the embolus entering each branch. This is some- 
times called a riding embolus. When smaller and softened, as 
in septic emboli, they pass into the smaller arteries of an organ, 
and then into the capillaries. Large emboli may be either non- 
infective or infective ; small emboli are usually infective. 

Certain arteries are more frequently blocked by emboli 
than others, though perhaps no great stress is to be laid on 
this order of frequency. Whether the embolus lodges or not 
in a particular artery appears to depend on the size, consistence, 
and shape of the embolus. Emboli are more frequently found 
in the renal, splenic, and cerebral arteries; next in order of 
frequency come the arteries of the lower and upper limbs, the 
celiac axis, the central artery of the retina, the superior and 
inferior mesenteric arteries, the abdominal aorta, and the 
coronary arteries. 

Embolism from the venous circulation and from the right 
side of the heart affects the pulmonary artery and lungs almost 
exclusively, except in the case of crossed embolism. Large 
emboli become blocked in the large branches of the pulmonary 
artery; small emboli are lodged in the smaller vessels. The 
emboli may be either infective or non-infective. 

Results of Thrombosis and Embolism. — The occurrence of 
thrombosis in the heart is a sign of embarrassment of the 
circulation of blood in the organ, but does not, of itself, pro- 
duce any definite effect, unless a clot be detached and become 
impacted in the mitral orifice, an event of very rare occurrence 
which leads to sudden death. The effect of complete stoppage 
of an artery, either by a thrombus or by an embolus with sub- 
sequent thrombosis, depends on the position and anastomoses 
of the vessel. If, as in certain localities, there is free anasto- 
mosis between the different arterial branches, no particular dis- 
turbance of the circulation in the part results. This is observed 
in the skin, in bone, and in such organs as the thyroid and 



RESULTS OF THROMBOSIS AND EMBOLISM 349 

uterus. Sudden stoppage of the circulation through the 
abdominal aorta is incompatible with life. It leads to rapid 
necrosis and desquamation of the epithelium of the intestinal 
tract, as well as to paralysis of the lower limbs. When 
the chief artery of a limb is completely blocked, the result 
and effect depend on the completeness of the collateral 
supply. Thus, circulation through the brachial artery may 
be stopped by aneurysm of the aorta and no great nutritional 
effect be noted in the limb, owing to the completeness of the 
supply through the circumflex and other arteries. This, how- 
ever, only occurs if the stoppage be gradual; and, in a sudden 
stoppage, in which the collateral supply has not had sufficient 
time to compensate, death of the part may ensue. 

In all cases of plugging of arteries, with the exception of 
such a large trunk as the main trunk of the aorta, completeness 
of the collateral circulation, to a great extent, determines the 
result: for if a small artery be plugged, and sufficient blood 
can enter the tissue through the collateral vessels, no damage 
to the tissue may result. If, however, the blood supply is not 
sufficient through the collateral circulation, the cells of the 
tissue are affected, and become atrophied, or undergo fatty 
degeneration; or, as in the more sudden forms of stoppage 
of the circulation, undergo coagulation necrosis. In addition, 
the tissue may become suffused with blood, owing to the 
diapedesis of the red corpuscles through the vessel wall. 

The sensitiveness of tissues to the stoppage of the blood 
supply varies considerably. Nervous tissue is perhaps the 
most sensitive (Chapter XIX.). and renal tissue comes next. 
Blockage of one carotid by an embolus will lead to well-marked 
degeneration of the cerebral hemisphere on the same side, as 
the circle of Willis does not insure a supply to the part by 
means of the other carotid and the two vertebral arteries. The 
renal epithelium dies in from one and a half to two hours after 
the blood supply is cut off (Litten). 

Infarction. — In the acute forms of arterial obstruction, such 
as occurs in embolism and thrombosis, the result is frequently 
the production of an infarct in the affected tissue. Infarcts 
occur in the lung, spleen, kidneys, and intestines, rarely, if 



350 CHANGES IN THE BLOOD IN DISEASE 

ever, in the liver, owing to the free anastomosis of the vessels. 
They are either red (hemorrhagic) or white (anemic) ; infec- 
tive or non-infective. 

Dealing now only with the non-infective infarcts, the mode 
of formation of the hemorrhagic infarct of the lung, spleen, 
and intestines, and of the white or anemic infarcts of the 
kidney and spleen has to be considered. Infarcts are usually 
w r edge-shaped, coming to the surface of the organ, from which, 
when recent, they project slightly; their wedge shape corre- 
sponding to the area of supply of the artery which is blocked. 
Hemorrhagic infarcts of the lung and spleen occur in mitral 
stenosis more particularly, and plugging of the artery may 
occur either by an embolus or thrombus. Cohnheim explained 
the formation of the hemorrhagic infarct by saying that after 
the blocking of an end artery (that is, an artery not joined by 
collaterals) there was a reflux from the veins which had no 
valves, leading to congestion of the affected area, and to a 
subsequent diapedesis of the red corpuscles which crowded the 
tissue (Fig. 102). It has, however, been shown that such a 
venous reflux is not necessary for the explanation of the occur- 
rence of an infarction. Thus, an infarction may be produced 
experimentally in the intestine of the dog, the veins of which 
have valves. Also if the artery is strictly terminal no hemor- 
rhagic infarction occurs, even if the vein has no valves; and 
the vein may be ligatured and an infarction experimentally 
produced. Thus, with regard to the kidney, infarction was 
produced after ligature of the right vein and artery, but it was 
prevented if the capsule were stripped, even though the vein 
remained pervious. The congestion in this case is produced by 
an afflux of blood from the capsule. If the access of blood is 
good, circulation is restored; if not, infarction occurs (Litten). 

These experiments emphasize the statement made previously, 
that the permanent effect on a tissue or part of the stoppage 
of the blood supply depends on whether the area affected can 
get a sufficiency of blood from the surrounding parts or not. 
In experimental infarction of the intestine, two or three hours 
after complete closure of the superior mesenteric artery, there 
is bloodlessness of the intestine, which is increased by its tonic 



RESULTS OF EMBOLISM 



35i 







Fig. 102. — Diagrams of the effect of embolism on the circulation. 
(Cohnheim.) 



The arrows represent the direction of the blood stream: (a) The nearest collateral 
arterial branch; (d) the nearest collateral -venous branch; (c) is the embolus itself. 

The diagrams represent the experiments which were performed with small emboli 
of wax on the vessels of the tongue of the frog. 

A is a diagram showing the changes in the circulation when the embolism is pro- 
duced slowly. In this case there is no sudden stoppage of the circulation, but the 
irregular embolus entering the arterial branch at first does not completely block it, 
so that there is a slight blood stream round its edges. There is obstruction to the 
circulation, and what happens is that the red corpuscular element of the blood is grad- 
ually removed by the collateral arterial and venous streams, leaving only a clear 
plasma in the vessels with obstructed circulation. This is shown in the figure by the 
vessels being left white. 

B represents a further change in the slowly produced embolism. There is a reflux 
•Of venous blood, as shown in the figure, into the parts containing the obstructed 
vessels, leading to an infarction. 

C represents the effects of a sudden embolism. In this case the blood stagnates in 
both artery and vein on the distal side of the embolus, and, finally, coagulation occurs, 
the red corpuscles not being removed, as in the slowly produced embolism. 

D represents the effects of an embolism when the obstructed vessel anastomoses 
with the neighboring vessels. It is seen that there is a clear plasma zone between the 
•embolism and the main vessel. On the distal side of the embolus as far as the col- 
lateral artery (d). the blood stagnates and coagulates, while the circulation of the 
part is but little affected, owing to the free anastomosis. 



352 



CHANGES IN THE BLOOD IN DISEASE 



contraction. Sudden and complete stoppage of the arterial 
supply to a loop of intestine is followed by infarction, as shown 
by hemorrhage and necrosis. The blood which is the source 
of the hemorrhage comes from the anastomosing arteries; 
and not by reflux from the veins, and the hemorrhage by 
diapedesis is the result of the stasis of the circulation (Welch 
and Miall). The hemorrhage which occurs in an infarct, 
although a prominent, is yet only a secondary change. The 
chief result of the complete and sudden blockage of the 
arterial supply to a part is necrosis, or death of the tissue 
(p. 214). This is seen in the further changes which take place 
in the hemorrhagic infarct. It becomes encapsuled with 
fibrous tissue, as if it were foreign matter. The coloring 
matter is absorbed, after disintegration of the red corpuscles, 
and the affected area becomes fatty, and, if small, is not infre- 
quently absofbed, leaving a scar. In the lungs these changes 
are not commonly observed, inasmuch as the infarcts are mul- 
tiple, frequently very large, and occur at a stage of the disease 
when the patient does not survive. In the spleen and kidneys, 
however, these changes are seen. 

In the white or ariemic infarct hemorrhage is absent, and 
necrosis is a prominent feature. These are observed mainly 
in the kidney, and the result of suddenly cutting off the blood 
supply is death of the cells of the tubules, which undergo coag- 
ulation necrosis (p. 215). The change is due to the coag- 
ulation of the protoplasm of the cell itself, and not to that of 
any surrounding liquid, as is sometimes stated. 

In the brain, as the result of embolism, a similar necrosis 
is observed. It, however, does not consist in coagulation of 
the protoplasm, but is a slower process and results in softening 
of the affected area. 

Infective Embolism, — The embolus invaded with micro- 
organisms may be either large or small. It may come from 
a thrombus in a large vein, or from a clot in a small vein 
leading from an infective focus. It may also come from the 
vegetations of the heart in ulcerative endocarditis, and . bac- 
terial emboli not infrequently arise from an infected area 
opening into an artery or vein. The large infective emboli 



AIR EMBOLISM 353 

will, in the first instance, produce the same lesion as a non- 
infective; that is, an infarction in one or other organ; and 
frequently, at death, it is impossible to distinguish the two 
varieties of infarction by a mere naked-eye inspection. If, 
however, the individual has survived sufficiently long, the 
infective infarcts undergo softening, either suppurating or 
showing a colliquative necrosis. With the smaller infective 
emboli, and with emboli composed of bacteria, definite in- 
farction may not be observed, but, round the area where 
they lodge, inflammation occurs, ending in suppuration or in 
softening (p. 123). 

Air Embolism. — The presence of air in the circulating 
blood results during the course of operations on the head 
and neck, in which the external air is sucked into the veins 
and sinuses. The air, if in large quantity, is carried to the 
right side of the heart and to the lungs. As a rule, it does 
not pass through the lung capillaries. If in large quantity, 
it causes paralysis of the right side of the heart, owing, it is 
said, to the air and blood being churned. It blocks the 
capillaries of the lungs, and death may result from paralysis 
of the right side of the heart, and from ensuing cerebral 
anemia. The results of air embolism appear to be due, not 
so much to the quantity of air introduced as to the suddenness 
of its introduction. Thus, in large animals, such as horses 
and dogs, large quantities of air have been experimentally 
introduced into the circulation, and have caused no appreciable 
change if the introduction is slow. Air embolism has been 
supposed to result from intra-uterine injections after parturi- 
tion, but this is doubtful. 

The presence of bubbles of gas in the blood and organs at 
death does not necessarily show the presence of air. In 
" caisson " disease, in which sudden death occurs in divers 
who are exposed in the apparatus to a heightened atmo- 
spheric pressure, the result has been ascribed to liberation 
of bubbles of nitrogen in the circulating blood, owing to the 
sudden relief of pressure. Bubbles of gas may be found in 
the blood of the heart and veins after death, and in some of 
23 



354 CHANGES IN THE BLOOD IN DISEASE 

these cases, when death has been ascribed to air embolism, the 
gas has been shown to be produced by a micro-organism, the 
bacillus aerogenes capsulatus (Welch). It is evident, therefore, 
that bacteriological examination is necessary before the source 
of bubbles of gas in the blood at death can be determined. 

Fat and Other Forms of Embolism. — Fat embolism is not 
infrequently observed, and may or may not produce appreci- 
able effects. It results from the entrance of liquid fat into 
ruptured blood vessels, usually veins, and is in the majority 
of instances caused by injury. Thus, it occurs from fracture 
of long bones, in diseases of the bone marrow, in softening 
of the brain, and in fatty liver. A condition of lipemia 
or excess of fat in the blood is observed in diabetes, as 
well as in other conditions, such as Bright' s disease, but no 
obvious effects are to be attributed to the presence of this 
fat in the blood. In fat embolism the liquid fat usually 
enters the venous circulation, and is carried to the right side 
pf the heart, whence it is sent to the lungs, which retain 
most of it in the small arteries and capillaries. Some, how- 
ever, passes through the capillaries of the lungs, and is 
distributed mainly to the brain, heart, and kidneys. The 
fat being itself non-infective, the effects of the embolism are 
mainly mechanical. If the fat is very large in amount, the 
result in the lungs and brain is edema and numerous ecchy- 
moses. In the heart and kidney cortex fatty degeneration 
results, owing to the interference with the local blood supply. 

Other and rarer forms of embolism occur when the cells of 
an organ or tissue enter the circulating blood. Thus, in some 
cases of injury of bone, or of disease, such as leukemia, bone 
marrow cells may be found in the capillaries, as well as liver 
cells in degeneration of the liver, and cells of the spleen may be 
found in the liver in cases of malaria. Cells of tumors may 
be also carried in the circulation to distant parts. As a rule, 
this form of embolism produces no result. It is only small in 
amount, and the cells undergo atrophy. In some cases, how- 
ever, a thrombus is formed round the embolic cells, and may 
even produce an infarction. 



CHAPTER XIV 

HEMORRHAGE AND PIGMENTATION 

Hemorrhage. — Cases of hemorrhage may be divided into 
two classes. In one there is a solution of continuity in the wall 
of the vessel. This is hemorrhage per rhexin, and the whole 
blood escapes, the corpuscles as well as the plasma. In the 
other form of hemorrhage there is no observed lesion of the 
wall of the vessel, but there is diapedesis of red corpuscles 
through the vessel wall, with a certain amount of plasma ; this 
is hemorrhage per diapedesin. Hemorrhage per rhexin may 
occur in arteries, capillaries, or veins. Hemorrhage per 
diapedesin can only occur in the smallest vessels (arteries or 
veins) or capillaries. 

A. The causes of hemorrhage may be usefully tabulated as 
follows : 

Causes of Hemorrhage. — i. External causes, or those arising 
outside the tissues, (a) Traumatism, whether due to mechani- 
cal injury, the passage of a urinary calculus, or the bites of in- 
sects and worms, such as the anchylostoma duodenalis, which 
causes intestinal hemorrhage, and bilharzia hematobia, which 
causes hematuria, (b) Ulcers of the skin and stomach or intes- 
tinal tract and malignant growths, which invade the vessel wall. 

2. Spontaneous hemorrhage, resembling those of the first 
class, but arising in the tissues, (a) Hemorrhage from an- 
eurysm of the systemic or pulmonary arteries; or from miliary 
aneurysm, (b) Hemorrhage from the lungs (hemoptysis) in 
early tuberculosis and other lung affections and in cardiac 
disease, (c) From the heart; in fatty degeneration, abscesses, 

355 



356 HEMORRHAGE AND PIGMENTATION 

and localized myocarditis, (d) From diseased veins of the leg 
(varices), and of the rectum (hemorrhoids). 

3. Hemorrhage occurs as the result of dry cupping. In the 
same class may be placed the hemorrhage which occurs in 
asphyxia, tetanus, strychnin poisoning, whooping-cough, and 
eclampsia. 

4. Toxic hemorrhages, which occur in certain forms of 
poisoning and acute infective disease. The mineral poisons lead- 
ing, by their general action, to hemorrhage are lead, antimony, 
and mercury (both acute and chronic poisoning), the intestines 
in the case of the last being chiefly affected. Organic poisons 
leading to hemorrhage are : Some forms of snake-venom, abrus 
poison, and some bacterial poisons, including putrefactive prod- 
ucts ; toxemic diseases of the liver, such as acute yellow atrophy 
and icterus gravis; infective diseases, such as typhus fever, 
ulcerative endocarditis, yellow fever, septicemia, congenital 
syphilis, and the hemorrhagic forms of variola, scarlet fever, 
diphtheria, and typhoid fever ; also the toxic conditions known 
as purpura and scurvy. Probably in this class come some of the 
cases of hemorrhage occurring in newly born children. 

5. Profound anemias, such as pernicious anemia, advanced 
secondary anemias, and leukemia. 

6. Hemophilia, or the hemorrhagic diathesis. 

7. Neuropathic hemorrhage, such as occurs in the lungs, 
and from the nose and stomach, in acute nerve conditions 
(apoplexy, epilepsy). 

Hemorrhage is either arterial, venous, or capillary. It is 
called parenchymatous when it occurs in the solid tissue 
of an organ. It may cover a small area, when it is referred 
to as petechiae or ecchymoses. It may be suffused through 
an organ, and is then referred to as hemorrhagic suffusion. 
Hemorrhagic infarction is a local hemorrhage, following the 
blocking of an artery (p. 350). Hemorrhagic focus is also a 
term used, and the term hematoma is applied to a hemor- 
rhagic focus forming a palpable mass. Blood discharged from 
the body receives special names, such as the blood of 
hemoptysis, from the lungs; hematemesis, from the stomach; 
melena, from the rectum; hematuria, from the urinary tract; 



BLOOD PRESSURE AND HEMORRHAGE 357 

and menorrhagia and metrorrhagia, from the uterus. These 
terms, however, are of clinical and not pathological significance. 
In discussing the causes of hemorrhage, the distinction 
of hemorrhage per rhexin from hemorrhage per diapedesin 
must be borne in mind. Clear examples of hemorrhage 
per rhexin are those due to traumatism, to the passage of a 
urinary calculus, or to the other causes mentioned in the first 
class in the list. In the other classes, examples of both 
rhexis and diapedesis occur. The occurrence of hemorrhage 
has to be studied in connection with the degree of blood 
pressure — arterial, venous, or capillary — and of disease of the 
vessel wall. Both these causes frequently act together in 
inducing hemorrhage. 

The Effect of Blood Pressure: Arterial. — No increase 
of the arterial blood pressure, within the limits occurring in 
the living body, will cause rupture of a normal artery. The 
normal carotid can withstand fourteen times the normal pres- 
sure without rupture. Spontaneous hemorrhage, therefore, 
resulting from a ruptured artery, depends not only on the 
blood pressure, but on another factor, disease of the vessel 
wall. In the systemic arteries, spontaneous hemorrhage occurs 
with an increase of blood pressure, most commonly in miliary 
aneurysms of the small arteries of the brain; the rupture of 
a large aneurysm is frequently initiated by a sudden exertion, 
which momentarily increases the arterial pressure. Perma- 
nent increase of arterial pressure, such as is observed in gran- 
ular contracted kidney in association with hypertrophy of the 
left ventricle, is constantly associated with hemorrhage which 
occurs in the retina, in the brain, and from the kidneys, and 
in all these cases there is disease of the vascular wall as well 
as a high arterial blood pressure. 

In the pulmonary arterial system an increase of the arterial 
pressure is constantly associated with hemorrhage from the 
lungs. Thus, in mitral stenosis, spontaneous hemorrhages 
occur from rupture of the pulmonary capillaries, and even of 
the arterioles. In aneurysm of the pulmonary arteries in 
tuberculous cavities of the lung it occurs frequently. The 



358 HEMORRHAGE AND PIGMENTATION 

spontaneous hemorrhage following the rupture of the vessel 
is due to a momentary increase of the arterial pressure caused 
by some sudden exertion, or a fit of coughing. 

Venous Pressure. — The jugular vein will rupture only if a 
hundred times the normal pressure is applied to it. The rupture 
of a large vein in disease depends on disease of the vessel wall, 
and on no mere increase of the venous pressure. The hemor- 
rhage occurring from varices of the leg or from the rectum is 
associated with disease of the vessel wall, aided by a local 
increase of the venous pressure, and is determined either by an 
Open ulcer or by traumatism. A general increase of the venous 
pressure, such as occurs in embarrassment of the circulation of 
the right side of the heart (as in mitral stenosis) and of the 
portal circulation (as in cirrhosis of the liver), is a factor in 
the spontaneous hemorrhage of hemorrhoids. 

Capillary Pressure. — An increase of capillary pressure, 
leading to hemorrhage, per rhexin or per diapedesin, occurs 
mainly when there is a retardation of the venous flow from 
a part. 

Disease of the Vessel Wall. — Disease of the vessel wall 
of an artery or vein, leading to the occurrence of hemorrhage, 
is of great importance, in association with an increase of the 
blood pressure. Atheromatous degeneration of a large or 
medium-sized artery does not, as a rule, lead to hemorrhage, 
unless an aneurysm is formed. This is, no doubt, due to the 
fact that, in many of these instances, the arterial blood pressure 
is not only not raised, but is actually lowered. In cases, how- 
ever of arterio-capillary fibrosis accompanied by high arterial 
tension the association of atheromatous degeneration, produc- 
ing as it does inelastic brittle vessels, is an important factor in 
the production of hemorrhage. It is commonly present when 
a high arterial pressure has existed for some years. With 
hypertrophy of the left ventricle, arterio-capillary fibrosis and 
high arterial pressure, numerous miliary aneurysms are found 
in the substance of the brain. These aneurysms owe their 
formation primarily to disease of the vessel wall, but also 
to the fact that the vessels lie in a perivascular space, thus 
allowing of the formation of a small dilatation. In the spinal 



HEMORRHAGE AND VASCULAR DISEASE 359 

cord these perivascular spaces are absent, so that the aneurysms 
are not formed. In granular contracted kidney the flame- 
shaped hemorrhages which occur in the retina are directly de- 
pendent on the degree of arterial pressure. They are asso- 
ciated with disease of the arteries of the retina, but are usually 
capillary or venous. Liability to their occurrence appears to 
be due to the fact that the vessels are less supported on one side 
than on the other. Hemorrhage from the kidney in granular 
contracted kidney is associated with the degree of high arterial 
pressure, but also with the acute and subacute congestions to 
which the diseased organs are liable. The disease of the 
arteries of the kidney, the contraction and degeneration of 
the glomerulus and the coincident degeneration of the kidney 
tubules explain the liability to hemorrhage on any sudden 
increase of arterial pressure, or any suddenly produced con- 
gestion. 

The importance of an increase of arterial pressure in the 
production of hemorrhage when the vascular wall is diseased 
is seen in diseases of the arteries other than those described. 
Thus, in syphilitic arteritis, in which there is localized disease 
of the vessel wall, there is no tendency to hemorrhage unless 
the arterial pressure be increased by some other cause, and 
the same may be said of atheroma. Disease of the vessel wall 
may itself, however, lead to hemorrhage without any increase 
of arterial pressure, when the wall is rapidly softened, as in 
embolic aneurysm and in infective arteritis. 

Degeneration of the pulmonary artery and its branches is 
observed when the pulmonary pressure is increased over a 
long period, as in mitral stenosis and other forms of obstruc- 
tion to the pulmonary circulation. In these cases, however, 
the arterial disease does not commonly progress beyond the 
formation of comparatively small fatty atheromatous patches 
in the intima of the vessels, and these do not appear to have 
any direct effect in the production of pulmonary hemorrhage 
or apoplexy. The hemorrhages which occur in the lung in 
prolonged increase of the pulmonary arterial pressure are 
mainly capillary, and are due to the rupture of these vessels, 
unsupported as they are by solid tissue. 



360 HEMORRHAGE AND PIGMENTATION 

Disease of the walls of the veins is an important factor in 
producing hemorrhage, and this need not be associated with 
any general or local increase of the venous pressure. Hemor- 
rhage from a venous trunk is usually produced by a lesion of 
the walls of the vessel by ulcer or traumatism. 

The conditions of hemorrhage which have just been dis- 
cussed do not offer any great difficulty in explanation. They 
comprise the first two classes given in the list. 

Asphyxial and Other Petechia. — Dry cupping, in which 
there is a sudden and great reduction of the atmospheric 
pressure over an area of the skin, leads to the occurrence of 
petechias in the subcutaneous tissues of the areas affected. 
Beneath the cupping glass it is seen that the skin is raised, 
owing to the reduction of pressure, and becomes dusky. 
There is thus an afflux of blood to the part which is not 
rapidly conveyed away. The occurrence of petechias has 
been ascribed to the sudden rise of arterial pressure in the 
part, causing an increased intracapillary pressure, and so 
rupture. This explanation does not appear, however, to be 
correct, and the petechias are probably traumatic in origin, 
the rupture of the capillaries being produced by their over- 
distention with blood, which ensues on the sudden reduction 
of pressure on the surface leading to retardation of the venous 
flow. 

Asphyxial petechias are observed in the lungs, pleura, and 
pericardium. Their constant occurrence in these parts points 
to some change in the thoracic circulation, produced by the 
asphyxial condition. In asphyxia there is cyanosis, which is 
due not only to the reduction of the amount of oxygen in the 
blood and the increase of carbonic acid, but also to venous 
stasis. The right side of the heart becomes embarrassed, so 
that all the thoracic organs are in a state of passive hyperemia. 
The production of petechias is not due simply to the state of 
congestion, but is the result of the powerful, repeated, and 
spasmodic attempts at respiration. The convulsive action of 
the diaphragm and the intercostal muscles, and of the accessory 
muscles of respiration, in their ineffectual efforts to get air into 
the lungs, converts the thorax into a large cupping glass 



TOXIC HEMORRHAGE 361 

(Cohnheim), the suction action leading to rupture of the capil- 
laries, and so to the production of petechia?. 

Asphyxial petechias occur elsewhere in the body, as do those 
which are observed in tetanus, strychnin poisoning, whooping- 
cough, and eclampsia. These occur in the muscles and in 
tissues of loose texture, such as the loose connective tissue of 
the conjunctiva. In the muscles the petechias are traumatic in 
origin, and are due to the convulsive contractions of the 
muscles. In loose connective tissue the hemorrhage may be 
in the form of petechias or of suffusion, and, in such cases, it is 
directly due to the condition of cyanosis and temporary in- 
crease of venous pressure leading to an increased intracapillary 
pressure and rupture of the capillary walls. 

Toxic Hemorrhage. — The hemorrhage which occurs in 
metallic poisoning, in poisoning by snake-venom, and in certain 
acute diseases, does not admit of a ready explanation. In the 
majority of instances there is no direct evidence of any gross 
lesion of the vascular wall. In these cases the hemorrhage 
occurs by diapedesis. In the hemorrhage of the intestine which 
occurs in poisoning by mercuric salts, the result has been 
ascribed to a fall of blood pressure, leading to increased capil- 
lary pressure, and so to hemorrhage. There is, however, no 
direct evidence of this, and it is possible that there is a direct 
effect of the poisonous salt on the vascular wall, leading to an 
increased permeability. In acute diseases there is, probably, a 
more profound effect on the walls of arteries, capillaries, and 
veins than is usually recognized, an effect which may be pro- 
duced by the invasion of the vessel wall by bacteria, or by the 
action of the poisons circulating in the blood. In these con- 
ditions rupture of the vessel wall may be observed, with the 
production of petechias in the brain, heart, lungs, liver, spleen, 
kidney, and gastro-intestinal tract. More commonly, however, 
there is no obvious rupture, and the wide distribution of the 
petechias, with the limited distribution of the bacteria, points to 
the profound effect of the circulating poisons on the vessels. In 
such cases it is supposed that the vessel wall shows increased 
permeability, and the hemorrhage occurs per diapcdesin. 

Large flat hemorrhages may occur in the subcutaneous 



362 HEMORRHAGE AND PIGMENTATION 

tissue, the loose subperitoneal tissue, in the mediastina and 
elsewhere in acute diseases, especially in the hemorrhagic forms- 
of the infective diseases. These are not obviously due to 
hemorrhage per rhexin, and appear to be induced partly by an 
effect on the vessel wall of the circulating poison, and partly 
by a profound change occurring in the composition of the 
blood, resulting in hemolysis (p. 329). In some of these 
cases, although the red corpuscles are present in the hemor- 
rhagic focus, the hemoglobin from many of them is liberated, 
staining the tissue. This liberation results from the destruc- 
tion of the corpuscles, which occurs in the blood stream itself. 

The relation of diminished coagulability of the blood to the 
occurrence of hemorrhage is not actually determined. It may, 
however, be that, in such conditions, blood more readily passes 
out of unruptured vessels. 

In the profound anemias, such as pernicious anemia, ad- 
vanced secondary anemia and the later stages of leukemia, 
hemorrhages occur, usually from mucous surfaces, such as 
the gums, nose, and gastro-intestinal tract. They also occur, 
though less frequently, in the brain and solid organs, and in the 
retina. In such conditions there is a profound change in the 
composition of the blood; there is a deficiency of oxygen and 
of hemoglobin, degeneration of the red corpuscles, and a 
diminished coagulability of the blood. The vascular wall is 
also affected, as shown by the fatty degeneration of the endo- 
thelial cells which occurs. The hemorrhages which occur, in 
all probability, are mostly per diapedesin. In some instances, 
however, they may be initiated by slight traumatism occurring 
in the gums near the tartar of the teeth, and in the stomach. 
It cannot, however, be said that, in most instances, traumatism 
plays a great part in the production of the hemorrhages. 
Obviously, it is absent in the production of the flame-shaped 
hemorrhages of the retina in pernicious anemia. 

In hemophilia the hemorrhages which occur are initiated by 
traumatism, and their continuance is due to a deficient coagula- 
bility of the blood, in the main apparently dependent either on 
a deficiency or an irregular combination of the lime salts. 

The hemorrhagic foci which are observed in the lungs in 



RESULTS OF HEMORRHAGE 363 

death from apoplexy, epilepsy, and in some cases of cerebral 
tumor and meningitis, and which may be referred to as neuro- 
pathic hemorrhage, are difficult of explanation, but are possibly 
initiated by sudden changes in blood pressure, brought about 
by a direct effect on the centers of the medulla. 

B. Results of Hemorrhage. — 1. Death from Hemorrhage 
may occur: (a) From copious and repeated loss of blood, 
whereby sufficient blood is not left in the body to carry on the 
vital processes; (b) by its effect on vital organs: this occurs 
when the hemorrhage takes place into the pericardium, from 
rupture of the heart, or an aneurysm, or by traumatism; or 
when it occurs in the brain, more particularly in the pons and 
medulla, and also when blood from a hemorrhagic focus in 
the cerebral hemispheres finds its way into the ventricles. 

2. The Spontaneous Cure of Hemorrhage per rhexin fre- 
quently occurs. Coagulation of the blood occurs outside and 
inside the vessel. At the site of the lesion, if small, a white 
thrombus is formed, preceded by the adhesion of the blood 
platelets to the sides of the lesion (Fig. 99). In a larger lesion, 
and with a copious loss of arterial blood, there is retraction 
of the arterial wall, followed by a lowering of the arterial 
pressure with a slowing of the circulation, these events tend- 
ing to cause a cessation of the hemorrhage. Experimentally, 
it has been found also that, towards the end of the bleeding, 
there is an increased coagulability of the blood, which may 
perhaps be produced by an increase of platelets, or by a libera- 
tion of fibrin ferment from the white corpuscles. 

3. Changes Occurring in the Extravasated Blood. — Blood 
extravasated in the tissues or from a mucous surface under- 
goes coagulation; for example, in the brain, in the subcuta- 
neous tissue, and from the stomach and other mucous surfaces. 
It may, however, remain fluid when slowly extravasated into 
joints and serous cavities. Absorption of the liquid parts occurs, 
with disintegration and absorption of the fibrin by means of?the 
phagocytic action of the white corpuscles, and, to some extent, 
of the tissue cells. The white corpuscles, for the most part, die; 
some become phagocytes (chiefly the mononuclear leukocyte), 



364 HEMORRHAGE AND PIGMENTATION 

taking up the disintegrating red corpuscles and fibrin. The* 
red corpuscles disintegrate, the hemoglobin diffuses. In? 
blood slowly extravasated into cavities, the oxyhemoglobin 
becomes reduced, and, if the medium is acid, as in the stomach 
and intestine, the coloring matter becomes dark or coffee- 
ground in appearance, and is precipitated as a chocolate-brown 
amorphous matter. 

In the tissues the hemoglobin may undergo one of several 
changes: into hematoidin crystals, hemosiderin, or pigment 
granules. 

Hematoidin (Fig. 103) is found in blood clots in the brain 
and elsewhere, in aneurysms, and in corpora lutea. It occurs 
either in brick-red rhombohedral crys- 



. #< b tals or as amorphous matter. It is in- 
?* Jk^ Sl^^ soluble in water, alcohol, ether, acetic 






.Hi 



acid, and dilute mineral acids or al- 
m * %f kalies : and is soluble only in concen- 
trated acids and caustic alkalies. It 
gives a play of colors with strong nitric 
crysTals I03 (i"L™" acid-Gmelin's reaction. It is free 
iology) from iron, and is chemically identical 

tais^hematowSr^ 1 S with bilirubin. It gives no absorption 

varying- in size, as well as U,.^ • + l, A enprtmm 
some amorphous masses, also LMTlUb m ine SpeCUlim. 

composed of hematoidin. Hemosiderin is a derivative of hemo- 

globin, containing iron and found not only in extravasa- 
tions and in thrombi, but in the liver, spleen, and kidneys in 
pernicious anemia. In the liver (Fig. 104) it occurs chiefly 
in the outer zone of the lobules, and is demonstrated by treat- 
ing sections of the organ with a 5 per cent, solution of ferro- 
cyanid of potassium, followed by a 1 per cent, solution of 
hydrochloric acid. This gives the Prussian blue test for iron. 

Pathological urobilin (see Urine, p. 402) is found in the 
urine after extensive extravasations of blood. The urine 
passed is dark, like jaundiced urine. The substance is probably 
identical with normal urobilin. It is soluble in alcohol, acids, 
and acidulated water; it is partly soluble in ether and ben- 
zine. In acid solution the spectrum shows a band close to F. 

The formation of brown pigment granules and flakes follows, 



PIGMENTATION 365 

in some instances, the extravasation of blood, especially if it 
is small in amount. The pigment is both extracellular and 
intracellular. The mononuclear leukocytes take up the red 
corpuscles, and pigment is formed inside the corpuscles., which 




£ B r g 



Fig. 104. — Hemosiderin in the liver in pernicious anemia. 

A transverse section of a liver lobule is shown with the central vein. Surround- 
ing it is a clear area of liver substance unpigmented and unstained. The liver cells 
outside this area show numerous black granules, which, in the fresh section, are 
greenish-blue. 

The specimen was stained with ferro-cyanid of potassium and hydrochloric acid 
for free iron. 

ultimately disappear, leaving the pigment free. The same 
process occurs with the tissue cells, and pigment granules may 
be carried to the nearest hmrphatic gland. The formation 
of pigment granules from the hemoglobin of the exuded red 
corpuscles is more commonly observed in inflammatory areas 
in the intestine, peritoneum, lungs, and pleura. 



366 HEMORRHAGE AND PIGMENTATION 

Large hemorrhages incite, even when non-infective, sur- 
rounding inflammation. The hemorrhagic focus may organize, 
by granulation tissue passing into it from surrounding healthy 
tissue. The hemorrhage may itself destroy the tissue invaded, 
and, if no infection occurs, the tissue atrophies and a scar is 
left. In some cases, the hemorrhagic focus forms a cyst, for 
example, in the brain (apoplectic cyst). A fibrous capsule 
is formed round the hemorrhagic focus, which ultimately 
softens, the cells degenerating and the hemoglobin undergoing 
the changes already described. Invasion of a hemorrhagic 
focus by bacteria may occur; either putrefactive or pus micro- 
organisms. Putrefaction affects the contents of the hemor- 
rhagic foci, whereas pus is formed in the periphery of the 
focus, and is discharged into the hemorrhagic area. Putre- 
faction and pus formation are liable to occur when the hemor- 
rhage is near an external surface, such as the mouth, in the 
lungs or pleura when the focus opens into a bronchus, in or 
near the vagina, or near the alimentary tract. 

Morbid Pigmentation. — Pigmentation, as met with in dis- 
ease, may be divided into two classes — true and false. True 
pigmentation results from an increase of the normal pigment 
in the body or is due to a pigment derived from the blood. 
Other forms of pigmentation are called false. 

True Pigmentation. — i. Increase of the Normal Pigment. — 
The pigment normally is contained in the cells of the rete 
Malpighii of the skin, of the retina, pia mater, choroid, 
sclerotic, and heart muscle. The pigment of the heart 
muscle is increased in various forms of degeneration and in 
cachexia. This is sometimes referred to as brown atrophy 
of the heart (p. 239). The amount of pigment in the skin 
varies normally within wide limits. It is, however, increased 
in Addison's disease, more particularly over the parts exposed 
to pressure, and pigment also appears in the buccal mucous, 
membrane. The skin pigment is increased in certain chronic 
inflammations of the skin, such as that produced by phthei- 
riasis; this increase of pigment is due to irritation. In 



PIGMENTATION 367 

pregnancy the skin becomes pigmented, especially about the 
face, and in exophthalmic goiter patchy and varying pig- 
mentation may be observed on the hands, head, and neck. 
In melanotic sarcoma and carcinoma arising from the skin 
and retina, the pigment of the primary growth is repeated and 
reproduced in the secondary growths. 

2. Hematogenous Pigmentation, or Pigment Derived from 
the Blood. — (a) This may result from extravasation of blood 
(p. 364) ; (b) or from the destruction of red corpuscles inside 
the vessels. The condition of hemoglobinemia produced by 
the liberation of hemoglobin in the blood is discussed in 
another chapter (p. 325). This is not the same condition as 
that. which obtains in malaria, in which pigmentation of the 
spleen, liver, brain, and other parts occurs. In this case the 
malarial parasite forms the pigment (insoluble melanin) 
during its process of growth, and during the destruction of 
the red corpuscle. The formation of hemosiderin in the liver, 
more particularly in pernicious anemia, has also been referred 
to (p. 364). In this case it is probable that the liver is the 
chief agent in destroying the red corpuscles and causing the 
•deposition of the hemoglobin derivatives. 

3. False Pigmentation requires but little explanation. It 
is such as occurs post-mortem in the black color of the liver 
and intestine, due to the formation of iron sulphid by the 
sulphureted hydrogen liberated during decomposition. 

Jaundice is also an example of false pigmentation, due to 
the bile coloring material. The yellow color of the tissues 
and skin in cachexia and profound anemias is due to the 
excessive formation of the coloring matter of fat (lipo- 
chrome). Pigment in other matters introduced into the 
body also causes false pigmentation, such as tattoo marks, 
the inhalation of coal dust, iron, and other matters into the 
lungs, and the prolonged administration of nitrate of silver, 
which produces a blue discoloration of the skin, a condition 
known as argyria. 



CHAPTER XV 

THE EFFECT OF DISEASE OF THE LIVER 

I. Changes in the Biliary Secretion; Jaundice — Variations in 
the Secretion of the Bile — Gall-stones. 

A. Jaundice. — Jaundice is a condition in which the bile 
coloring matter, bilirubin, is present in the tissues which are 
stained green, brownish-green, or, in prolonged cases, a black- 
ish-green color. The tissues which are stained are the skin, 
conjunctivae, and the connective tissues generally; the mucous 
membranes are not stained unless they are inflamed, and the 
coloring matter is not present in the secretions of the digestive 
juices, or in the tears. The bilirubin is excreted in the urine, 
which varies in color from greenish-yellow to black. Bilirubin 
is also excreted from the skin. If the bile does not enter the 
intestine at all, the motions are clay-colored and frequently 
show glistening particles of fat. 

The physiological effects of the presence of bile in the tissues 
in jaundice are but slight. Itching of the skin is sometimes 
present, and yellow vision and xanthoma have been ascribed to 
the conditions somewhat doubtfully. To the presence of the bile 
acids in the circulation, the slowing of the pulse (bradycardia) 
which is sometimes observed, is ascribed, as well as the slight 
increase in the arterial blood pressure. It is doubtful whether 
bilirubin possesses any poisonous action. Intravenous injection 
in rabbits has been said to produce death with an effect on the 
kidneys, heart, and central nervous system. The method used 
for preparing bilirubin was, however, open to objection, all the 
bile salts not being removed. The bile acids and salts have a 
distinct physiological action. Injected subcutaneously or intra- 

368 



BILIRUBIN AND BILE SALTS 369 

venously, they produce slowing of the heart's action, with con- 
vulsions, ending in coma and death. Outside the body they 
have a hemolytic action on the red corpuscles ; but it is perhaps 
doubtful whether this action takes place in disease, as in jaun- 
dice the bile acids are never in sufficient quantity in the blood 
or tissues to produce their pronounced physiological action 

(P- 377)- 

The severe symptoms which are sometimes associated with 
jaundice are due, not to the condition itself, but to the disease 
producing the jaundice. The severest symptoms are observed 
in malignant jaundice (icterus gravis). This term is, however, 
a misnomer. There is no such thing as malignant jaundice. 
The cases referred to are those usually of severe infective dis- 
ease associated with jaundice as one of the symptoms. 

In discussing the causes of jaundice, it is necessary to bear 
in mind certain physiological facts relating to the formation of 
bilirubin and the bile acids, and to the circulation of the bile. 
Bile acids and bilirubin are made by the liver, and not by the 
blood and tissues, a fundamental fact to remember in the dis- 
cussion of those cases of jaundice which were formerly sup- 
posed to be hematogenous in origin. Nowhere in the body but 
in the bile secretion are bilirubin and bile acids found. 

Bilirubin (C 16 H ]8 N 2 3 ) is a derivative of hemoglobin, and 
is of the same composition as hematoidin (p. 364), the forma- 
tion of which is ascribed, not to cell agency, but to a purely 
chemical change occurring slowly in the hemoglobin of old 
blood clots. It is doubtful, however, whether under these con- 
ditions, cells are not the agents in forming the hematoidin. At 
any rate, in the liver the rapid formation of bilirubin must be 
due to the activity of the liver cells. Bilirubin is a substance 
insoluble in water, slightly soluble in alcohol and ether, readily 
soluble in acids and alkalies, chloroform and benzine. It is 
held in solution in the bile chiefly by the bile salts. It is iron- 
free, and shows no absorption bands in the spectrum, although 
the violet end of the spectrum is absorbed. It gives a play of 
colors with strong nitric acid, due to the formation of different 
colored oxidized derivatives (Gmelin's reaction). The green 
oxidized product is called biliverdin ; the yellow, choletelin 
24 



370 THE EFFECTS OF DISEASE OF THE LIVER 

(C 16 H 18 N 2 6 ). During the play of colors obtained by the 
nitric acid, the solution shows absorption bands in the spectrum, 
between D and F. 

The bile acids consist of taurocholate and glycoeholate 
of soda. Taurocholic acid is of the formula C 06 H 45 NO 7 S; 
glycocholic acid is C 26 H 43 NO e . The bile salts are special 
secretions of the liver. They are not found normally in the 
blood and tissues; they are present only in small quantity in 
the feces and in normal urine. 

Bile, the secretion of the liver, is discharged into the 
intestine, and plays a certain part in the processes of diges- 
tion. Some of the bile coloring matter is discharged in the 
feces as stercorin. Most of it is reabsorbed, and discharged 
in the urine as urobilin, some, no doubt, going back to the 
liver and being excreted again. But little of the bile salts is 
excreted; they are mostly reabsorbed and passed back to 
the liver, where they are possibly reconverted. There is, 
therefore, to some extent, a bile circulation from the liver to 
the intestines, and back again to the liver by means of the 
blood vessels. 

It is necessary to consider the physiological relations between 
bilirubin, hemoglobin, and the bile salts. Bilirubin does not 
exist in the normal blood, or, if present, it is in such small 
quantities as not to be detected by analysis. It is present, 
however, in the blood of the horse (Hammarsten). Bilirubin 
is a derivative of hemoglobin, and, although the transformation 
of hemoglobin into hematoidin — which is identical with bili- 
rubin — occurs in old blood clots, yet it must be considered that, 
normally, the liver is the only organ or tissue capable of manu- 
facturing bilirubin. Frerichs concluded that bile acids were 
converted into bilirubin in the body, the coloring matter being 
found in the urine after the injection of bile acids. It was 
shown, however, that the bile acids liberated hemoglobin from 
the blood corpuscles, so it was considered probable that the bili-, 
rubin was derived, not from the bile acids, but from this lib- 
erated hemoglobin (Kiihne). The injection of hemoglobin 
in solution into the circulation of dogs does not cause the 
appearance of bilirubin in the urine, as has been stated, but only 



JAUNDICE 371 

of hemoglobin. Subsequent researches confirmed the conclusion 
that the injection of hemoglobin or oxyhemoglobin, into the 
circulation of healthy animals, did not cause the appearance 
of bilirubin in the urine, but that it had the effect of increas- 
ing the amount of bilirubin in the bile, a similar event hap- 
pening if bilirubin were injected into the circulation. It has 
also been shown that the increase of bilirubin in the bile, 
following the injection of hemoglobin into the circulation, 
is not the result of the transformation of the one body into 
the other in the blood, but that the conversion takes place in the 
liver itself, the cells of which are observed inclosing the red 
corpuscles and the hemoglobin (Naunyn). Moreover, if the 
liver be extirpated, no bile coloring matter is found in the body 
(p. 384). It may be concluded that the presence of free hemo- 
globin in the blood may lead to hemoglobinuria or urobilinuria, 
and leads to an increase in the amount of bilirubin secreted by 
the liver, but not to the formation of bilirubin in the blood, or 
to its excretion in the urine. 

The results of these experiments have a direct bearing on the 
causes of jaundice. Jaundice has been divided into two classes 
— obstructive and non-obstructive. In the obstructive form, 
the bile is prevented from entering the intestine; it is therefore 
reabsorbed by the lymphatics of the liver and carried to the 
thoracic duct, and so into the venous circulation. The coloring 
matter stains the tissues in the manner already described, and is 
excreted in the urine with the bile acids. Obstructive jaundice 
has also been called hepatogenous. 

In non-obstructive or hematogenous jaundice, there was con- 
sidered to be no obstruction. Jaundice is less intense than in 
the obstructive form, and only the bilirubin, and not the bile 
acids, were described as excreted in the urine. 

This distinction of the two forms of jaundice in these terms 
is no longer admissible, and it is best to divide jaundice into : 

1. That caused by pressure on, or obstruction of, the ducts 
outside the liver. 

2. Pressure on the ducts inside the liver. 

3. Toxemic jaundice, or that due to poisoning of one form 
or another. 



372 THE EFFECTS OF DISEASE OF THE LIVER 

i. Affection of the Duct outside the Liver. — This occurs : 

(a) In gall-stones, by inspissated bile, by worms in the duct, 
and, rarely, by foreign bodies entering the duct from the intes- 
tine. Inflammation of the duodenum, and catarrh of the duct 
causing plugging by mucus, lead to the same result as the first 
of the causes mentioned. Stricture of the duct is produced by 
a cicatrized duodenal ulcer, by perihepatitis, or by a cicatrized 
ulcer of the duct itself, caused by a gall-stone. 

(b) Tumors at the neck of the gall bladder, passing down- 
wards, or situated at the orifice of the duct, are also causes. 

(c) Pressure from without is observed in tumors of the 
liver, stomach, pancreas, kidney, omentum, ovary, uterus 
(pregnant uterus), aneurysm, and fecal accumulation. 

2. Pressure on the Ducts in the Liver itself is observed 
mainly in cirrhosis of the organ, and in " nutmeg " liver 
(passive hyperemia). 

3. Toxemic Jaundice is observed as the result of : 

(a) The action of poisons, such as toluylene-diamin, phos- 
phorus, arseniureted hydrogen, pyrogallic acid, and snake- 
venom; and follows the injection of large quantities of distilled 
water into the circulation. 

(b) It is also observed in infective diseases, such as pyemia, 
yellow fever, malaria, relapsing fever, " epidemic " jaundice, 
Weil's disease (infective jaundice), "malignant" jaundice, 
and acute yellow atrophy of the liver. It is seen in rare 
cases of typhoid fever, typhus fever, pneumonia, and scarlet 
fever. 

1 and 2. The explanation of the cause of jaundice in the 
first two classes of cases is simple. The liver, being normal, 
continues its secretion of bile which, however, is unable, owing 
to the obstruction, to reach the intestine. It is therefore 
reabsorbed, appears in the tissues, and is excreted in the 
urine. The channel of absorption has been shown to be 
the lymphatics of the liver and the thoracic duct. Experi- 
mentally, after ligature of the common bile duct, jaundice 



CAUSES OF JAUNDICE 373 

supervenes, but this does not occur if, at the same time, the 
thoracic duct be ligatured, or an opening be made into it. 
The jaundice persists in these cases, and is intense as long 
as the obstruction lasts. Variations in the intensity of the 
condition are, however, observed. The motions never become 
of a normal color, remaining clay-colored, but the actual 
coloring of the skin and the amount of coloring matter observed 
in the urine vary in prolonged cases to a considerable ex- 
tent from time to time. This is due to the fact that the 
amount of bile secreted by the liver in such cases varies consid- 
erably, especially if there be pyrexia, or the liver substance 
be damaged. In some cases of cirrhosis of the liver there 
is but little or no jaundice, even though the condition 
has lasted for some time. This means either that a dimin- 
ished amount of bile is secreted or that the obstruction is 
not sufficient to cause the absorption of a large quantity of the 
secreted bile. In some cases, on the other hand, the jaundice 
is intense, and lasts for a long period, and, even when absent in 
well-marked cirrhosis, it usually appears towards the end of the 
disease. 

3. Toxemic jaundice is the result of the action of poisonous 
substances, and so, unlike the first two classes of cases, it is 
accompanied by severe symptoms, due to the physiological 
effect of the poison on other organs and tissues. Thus, it is 
accompanied by pyrexia, and by the signs of an action on the 
nervous system, such as stupor, coma, twitchings, and convul- 
sions. In this form of jaundice there is no obvious obstruction 
to the flow of bile in the bile ducts. 

The earliest theory of the explanation of toxemic jaundice, 
due to Morgagni and Boerhaave, ascribed the condition to the 
fact that the biliary constituents were not eliminated, and so 
accumulated in the blood. It is quite possible to suppose that 
a transient jaundice might be due to the accumulation of the 
bile constituents in the blood, but only in the event of the 
liver and kidneys being damaged by disease. A subsequent 
theory was that of Frerichs, who considered that there was 
a diminished oxidation of the bile constituents which were 
absorbed into the circulation from the intestine, so that they 



374 THE EFFECTS OF DISEASE OF THE LIVER 

accumulated in the body, and that the condition was also 
associated with an increased secretion of bile, or polycholia. 
Frerichs' theory was, however, based upon erroneous data, the 
chief of which was that the bile acids were convertible into 
bilirubin. 

The more modern idea of the causation of toxemic jaundice 
is that it is due to a temporary obstruction to the flow of bile 
in the smaller bile ducts. The bile is secreted normally at a 
very low pressure, so that any general cause which obstructs 
(even temporarily) the flow of bile in the small bile ducts will 
cause an absorption of the bile by the lymphatics, and so a 
slight, and often temporary, jaundice. The jaundice, in these 
cases, is associated with the action of a poison, and the actions 
of some of these poisons have been investigated, with the fol- 
lowing results. Toluylene-diamin is a poisonous substance, 
which, injected into dogs, causes both hemoglobinuria and 
jaundice. The action on the secretion of bile may be divided 
into two stages. In the first the bile is increased in quantity, 
that is, there is polycholia ; in the second the bile is diminished, 
and becomes more like viscid mucus. The secretion then 
regains its normal character, as the action of the poison dimin- 
ishes. Jaundice supervenes at the end of the first stage, con- 
tinues during the second, and disappears in the third. The first 
stage — that of polycholia — is, no doubt, associated with the 
destruction of red blood corpuscles. The stage of jaundice is 
associated with a viscid mucous secretion; this, temporarily 
leading to an increase of pressure in the bile ducts due to a par- 
tial obstruction of the smaller bile ducts, causes the jaundice 
which passes off in the third stage, as the secretion of bile 
becomes less viscid and more copious. 

The action of arseniureted hydrogen and of phosphorus 
in the production of jaundice is explained in the same way 
(Stadelmann), and it is to be noted that, after extirpation of 
the liver, arseniureted hydrogen causes the appearance of 
hemoglobin in the urine, and not bilirubin (Minkowski and 
Naunyn). 

It is of interest to note that dogs infected with piroplasma 
cants suffer from jaundice : while cows infected with piro- 



CAUSES OF JAUNDICE 375 

plasma bigeminum show hemoglobinuria (Texas fever). Both 
these organisms are parasitic in the red corpuscle, which they 
destroy (p. 152). 

The occurrence of jaundice in the infective diseases already 
enumerated has probably the same explanation, which is evi- 
dently a much simpler one than any other that has been 
advanced. The sequence of events may be summarized as fol- 
lows : the toxic substances liberate the hemoglobin from the red 
corpuscles ; the coloring matter is transformed by the liver, and 
so there is polycholia, or. at any rate, polychromia, that 
is, an increase in the coloring matter. This is soon followed,, 
however, by a second stage of viscid bile, which causes ari 
obstruction to the flow, and so leads to jaundice. As would 
be expected, the jaundice is, as a rule, slight, and markedly 
diminishes from time to time, even disappearing and re- 
turning. 

There are some cases of jaundice which cannot, at present, 
be included in any of the above classes. Infantile jaundice 
occurs soon after birth, and is, in some instances, due to 
organic disease. In other cases, however, no obvious obstruc- 
tion is present, and the jaundice has been ascribed to sudden 
changes in the hepatic circulation, or to a sudden polycholia 
leading to an absorption of the excess of bile by the lymphatics 
of the liver. Nervous jaundice has been described as following 
anxiety or sudden excitement. In these cases the jaundice 
supervenes suddenly after the initial cause, and is, as a rule, 
temporary. It has been ascribed either to spasm of the ducts, or 
to the absorption of the bile by the blood capillaries, and not 
by the lymphatics, the blood capillaries absorbing the bile, 
owing to a sudden fall of blood pressure in the portal system. 
It is. however, very doubtful whether the blood pressure in the 
liver capillaries could fall below the pressure of the bile in the 
bile ducts. 

Influence of Jaundice on Metabolism. — In jaundice, as a rule, 
a deficient amount of food is taken so that the amount of 
nitrogen in the urine is less than the normal, but the total 
output of nitrogen is greater than the intake, there being thus 



376 



THE EFFECTS OF DISEASE OF THE LIVER 



2l loss of nitrogenous material from the tissues. This is shown 
in the following table (Miiller, quoted by Von Noorden) : 





Number of 
Calories 

IN THE 

Daily Food. 


Daily Amount of Nitro- 
gen in Grams. 


The Amount 
of Nitrogen 




Absorbed. 


In Urine. 


Lost from 
Tissues. 


i. Man greatly emaci- ) 
ated; jaundice due I 
to gall-stones . . ) 


1082 


IO.19 


IO.85 


0.66 


2. Man, jaundice due ) 
to gall-stones; cir- >■ 
rhosis of the liver ) 


1610 


14. 1 1 


15.88 


1. -77 


The same .... 


883 


17.18 


17.14 


•• 



The amount of urea in the urine is not appreciably altered 
in jaundice. 

The absorption of the food products varies in jaundice. The 
absorption of carbohydrates and of proteids is but little, if at 
all, affected ; the chief effect is on the fat. Careful estimation 
of the amount of fat taken in with the food, and the amount 
passing undigested in the feces, has shown that in jaundice 
from 40 to 80 per cent, may be unabsorbed as compared with 
about 7 per cent, in healthy individuals on the same diet. 
The diet in the experimental cases, both of the jaundiced and 
healthy, consisted of milk, white bread, and butter. The fat 
which appears in the feces consists only of a small quantity of 
normal fat, and a large quantity of fatty acids combined with 
alkalies. It appears to be the contrary when the pancreatic 
juice is prevented from entering the intestine. In this case 
there is little fatty acid in the feces, the fat appearing chiefly as 
neutral fat. 

The persistence of jaundice has a deleterious effect on the 
activity of the liver cells, for although bilirubin continues to 
be secreted for long periods, yet the secretion of the bile 
acids diminishes. Normally, the bile acids are not destroyed 
in the blood or intestine, and being reabsorbed, pass again 
into the bile. In cases of jaundice they are but rarely found 



METABOLISM IN JAUNDICE 377 

in the urine, and if they were formed in normal quantity it 
is probable that they would produce toxic symptoms. It is 
rare, however, for any toxic symptoms as the result of poison- 
ing by bile acids to occur in cases of jaundice. The amount 
of bile acids present in the bile in long-standing cases of 
jaundice is diminished. Thus bile obtained from a biliary 
fistula in such a case was found to contain only 0.055 P er 
cent, of taurocholate of soda and 0.165 P er cent - °* g!y co ~ 
cholate of soda, the normal amount of bile salts being 2 per 
cent. 

In the jaundiced liver, the amount of glycogen is somewhat 
diminished, but glycosuria is rarely present either in jaundice 
or in other diseases of the liver. It is very doubtful if sugar 
appears in the urine even if large quantities of glucose are given 
daily — 100 to 200 grams — although a positive result has been 
stated to have been obtained. 

B. Variations in the Secretion of Bile in Disease. — The bile 
may undergo either an increase or diminution in quantity, or 
one constituent, more particularly the bilirubin, may be dimin- 
ished, so that pale or colorless bile is secreted. In some 
instances substances not normally present in the bile have 
been observed. But little is known of the conditions in disease 
in which polycholia occurs. In most cases of disease of the 
liver leading to degeneration of the ceils, the bile is diminished 
in quantity or altered in quality. A rise of body temperature 
leads to the secretion of pale or colorless bile; this has been 
noted, also, in some cases of fatty degeneration of the liver. 
Albumin is present in the bile in some cases of Bright's disease, 
and after the injection of water into the blood. The injection 
of sugar leads to the presence of sugar in the bile, and 
this is also observed in diabetes. The bile may contain an 
excess of urea, as in Bright's disease and in cholera; and in 
cases of acute yellow atrophy of the liver it contains leucin 
and tyrosin. as do many other liquids of the body in that dis- 
ease. Hemoglobin has been found in the bile (hemoglobin- 
cholia), as the result of the action of the poisons which also 
cause jaundice. Thus it occurs from the action of toluylene- 



378 THE EFFECTS OF DISEASE OF THE LIVER 

diamin, pyrogallic acid, phenylhydrazin, potassium chlorate, 
and aniline compounds (Filehne). 

The action of drugs on the secretion of the bile has given 
rise to much discussion and experiment. For a complete dis- 
cussion of this subject, works on Pharmacology must be con- 
sulted. It may here be stated, however, that the latest 
researches tend to negative the idea that any of the so-called 
cholagogues actually stimulate the secretion of bile by the liver, 
but to show that there is an increased secretion when bile itself 
is administered. 

The Secretion of the Gall Bladder. — The gall bladder is a 
receptacle for the bile, but its mucous membrane has a secretion 
of its own, the chief constituent of which is called " mucin,'' 
or, more accurately, nucleo-albumin. In dropsy of the gall blad- 
der (hydrops cystidis felleae), which results from permanent 
obstruction of the cystic duct, the liquid found is clear and 
viscid. The discharge, in a case of fistula, gave the following 
analysis: Specific gravity, 1009.5; total solids, 15.36; organic 
matters, chiefly "mucin," 6.72; chlorids (as NaCl), 5.73; 
sodium carbonate, 2.2 ; other salts (phosphates and potassium 
salts), 0.71 (Mayo Robson, quoted by Gamgee). This analy- 
sis probably represents the secretion of a diseased gall bladder, 
and not of a normal one. 

C. Cholelithiasis (Gall-stones). — Gall-stones are found 
mainly in the gall bladder, sometimes in the ducts within the 
liver, and sometimes in the common bile duct. In the latter 
case they always come from the gall bladder. They vary 
greatly in size, number, and chemical composition. The largest 
sized calculi may occupy the whole of the gall bladder, or there 
may be two large calculi. It is more common, however, to find 
several medium-sized calculi, and, although the number present 
may be in some cases reckoned by thousands, the average 
number is under twenty. 

The chemical composition shows they consist mainly of 
cholesterin, bilirubin-calcium, and calcium carbonate. Other 
colored derivatives of bilirubin may be present, such as bili- 
cyanin and choletelin, but gall-stones do not contain either free 



GALL-STONES 379 

bilirubin or the salts of the bile acids. Cholesterin (C„H 48 HO) 
is present in the bile, and is held in solution by the salts of 
the bile acids, by soaps and neutral fats. It is found also 
in many other tissues, such as the white matter of the brain 
and spinal cord and nerve fibers, and blood corpuscles. The 
amount present in bile varies considerably, from 0.05 to 0.35 
per cent. Cholesterin is very widely distributed in all cellular 
tissues, both animal and vegetable, and is probably an excretion 
of the liver. It is insoluble in water or saline solutions, but is 
readily dissolved by alcohol and ether. 

Bilirubin (p. 369) is insoluble in water, but is readily dis- 
solved by dilute solutions of caustic alkalies and ammonia. It 
is no doubt held in solution in the bile by the alkaline salts 
present and by the bile salts. The calcium compound which 
is present in gall-stones may be prepared artificially by precip- 
itating an alkaline solution of bilirubin with calcium chlorid. 
The precipitate is insoluble in water, alcohol, ether, and chlo- 
roform, and has the formula of C 32 H 34 N 4 6 Ca. 

The varieties of biliary calculi may be classified as follows 
(Figs. 105 and 106) : 




Fig. 105. — Gall-stones. 

A shows the soft crenated bilirubin-calcium stones, natural size. These are black 
when removed from the gall bladder, and are soapy to the touch. 

B repres2nts the common faceted biliary calculus, natural size. 

C represents a section of one of these calculi, twice the natural size. In the center 
is a bl ick mas-; of bilirubin calcium, with three or four cavities. Radiating from this 
to the periphery are fine needles of crystals of cholesterin, which are interrupted in 
parts by concentric dark rings of bilirubin-calcium. 

The periphery of the stone is formed by a white hard layer composed of phos- 
phate and carbonate of lime. 

I. Pure cholesterin calculi, which are known as biliary sand 
or pearls, and are usually seen as very light glistening yellowish 




380 THE EFFECTS OF DISEASE OF THE LIVER 

globules, without any internal structure, and completely soluble 
in alcohol and ether. 

2. Stratified cholesterin calculi, which may be very large, 
and which sometimes show a nucleus, from which radiate 



9 



Fig. 106. — Gall-stones. 

A represents cholesterin perles, natural size. They are glistening on this surface- 
and dissolve completely in ether. 

B is a section of a pure cholesterin stone twice the natural size (Naunyn). The- 
stone is seen to be composed almost solely of largish crystals of cholesterin. which 
interlace at the center of the stone, but radiate mostly to the periphery. At the per- 
iphery is a little bile coloring matter, and the surface of the stone is composed mainly 
of cholesterin, with some lime salts. 

closely packed crystals of cholesterin, arranged in layers. This, 
form of calculus may be very large, oval or globular. Analysis 
shows that they contain 65 to 98 per cent, of cholesterin, and 
from 1.5 to 2J per cent, of other organic matters, only a very 
small proportion of which is bilirubin. 

3. The commonest form of biliary calculus is yellow or 
whitish-brown, and is usually found multiple and faceted ; they 
may be soft when freshly obtained. On section, they show a 
central nucleus, which is commonly dark, and composed of the 
bile pigment in combination of calcium. The nucleus has also 
been found to be composed of inspissated mucus, degenerated 
epithelial cells, degenerated blood clot, or rarely a parasite 
such as a dried round worm (ascaris lumbricoides). The 
middle zone of the calculus is composed of concentric layers,, 
united by radiating crystals of cholesterin. This layer con- 
sists almost solely of cholesterin, but is colored in some- 
cases with bile pigment. The external layer of the calculus is- 
composed either of a mixture of cholesterin and bile pigment,, 
or of calcium carbonate mixed with pigment. 



GALL-STONES 381 

4. The calculi called mixed bilirubin-calcium stones are 
composed of bilirubin-calcium and cholesterin in varying pro- 
portions. They do not, however, show the structure of the 
ordinary calculus, although they may possess a nucleus of 
cholesterin. 

5. Pure bilirubin-calcium stones are not uncommon. They 
are usually small and soft. They consist almost solely of 
bilirubin-calcium and derivatives of the bile coloring matter, 
with only minute quantities of cholesterin. 

6. Calculi are sometimes found containing only traces of 
cholesterin and bilirubin, and consisting mainly of calcium 
carbonate, with a smaller quantity of calcium phosphate. 

7. Lastly, casts of hepatic ducts may be found, consisting 
mainly of inspissated bile. 

Mode of Formation of Gall-stones. — Gall-stones are more 
common in women than in men, in the proportion of three 
or five to one. The tendency to their formation also* increases 
with age, being most frequent at sixty years and over, and 
being very uncommon under twenty years of age. The tend- 
ency to the formation of gall-stones is not affected, apparently, 
by heredity, by diet, by the circumstances of life, or by the 
condition of fatness or spareness. It appears to be purely a 
local condition, induced by changes occurring in the bile in 
the gall bladder. The points for consideration are the con- 
ditions of precipitation of bilirubin, cholesterin, and calcium 
carbonate from the bile in the gall bladder. It is to be noted 
that these three substances are held in solution very lightly; 
bilirubin, by the alkaline salts of the bile, being readily precipi- 
tated by calcium ; cholesterin being held only lightly in solution 
by the bile salts; while calcium carbonate is, with difficulty, 
kept in solution by the carbonic acid present. It has been 
stated that calcium carbonate is secreted by the mucous mem- 
brane of the gall bladder (Frerichs), and it has been supposed 
that the precipitation of the bilirubin and of the cholesterin 
is due to the bile becoming acid, owing to an acid fermentation 
(Frerichs) . This acid fermentation can only occur by means of 
a micro-organism, and, in the majority of cases of gall-stones, 



382 THE EFFECTS OF DISEASE OF THE LIVER 

no acid-forming micro-organism is apparently present. It has 
again been supposed that the cholesterin is secreted by the 
epithelial cells in the gall bladder and bile ducts. This is in- 
creased when the epithelium becomes diseased. This theory 
of the formation of gall-stones (Naunyn) supposes that damage 
to the gall bladder is done by micro-organisms which enter by 
the common bile duct from the intestine, and consist mainly of 
the bacillus coli communis. It cannot be admitted, however, 
that it is proved that this condition is the most usual cause 
of the formation 6f gall-stones. 

The regular and complete emptying of the bladder during 
health would preclude the formation of gall-stones, so that one 
of the causes must be considered as a comparative stasis of 
the bile in the gall bladder, a stasis not necessarily due to any 
organic obstruction, but possibly due to a diminished contract- 
ility of the muscular wall of the bladder. This may be one of 
the factors explaining the increased formation of gall-stones as 
age advances, as it has been shown that the muscular fibers 
of the gall bladder undergo atrophy in old age (Charcot and 
Pitres). 

The occurrence of bilirubin-calcium in gall-stones must be 
considered as the result of a process of precipitation, and this 
precipitation might readily be initiated by the antecedent pre- 
cipitation of calcium carbonate through a diminution in the 
quantity of carbonic acid, the calcium combining with the 
bilirubin in the process of precipitation. In all liquids in which 
organic substances are held in solution very lightly, the pre- 
cipitation of one substance tends to the precipitation of another, 
so that the cholesterin might readily be deposited round the 
bilirubin-calcium nucleus. Precipitation of the cholesterin 
must, however, be considered a separate process from that of 
the bilirubin-calcium, and it may possibly be initiated by a 
diminution in the quantity of solvents, namely, the bile salts and 
the soaps. 

II. Disordered Functions of the Liver. — The functions of 
the normal liver may be given as follows : 
I. The secretion of bile. 



DISORDERED FUNCTIONS 383 

2. The storage of glycogen — the glycogenic function of 
the liver. 

3. The proteolytic function of the liver, whereby proteids 
are transformed or broken up, or non-proteid nitrogenous 
bodies are changed. Thus, the liver has to deal with the 
formation of urea and uric acid. 

4. The liver has a profound effect on certain poisons, 
which are absorbed into the system. Not only are certain 
poisons excreted in the bile, but some are actually destroyed 
by the liver. 

5. The hemolytic function of the liver. To the liver cells 
has been ascribed the important function of breaking down 
the hemoglobin of the red corpuscles, some of this hemo- 
globin going to the formation of bilirubin, the remainder 
being present in the organ as hemosiderin (p. 364). The 
hemosiderin is in some animals, for example, rabbits, in- 
creased by food, and is greatly increased in one disease, 
namely, pernicious anemia. 

The alterations of some of these functions in disease, 
namely, urea formation and the glycogenic function, are 
discussed in the chapter on Changes in Metabolism (p. 424). 
Hemolysis has already been discussed (p. 323). Here it is 
necessary to discuss the effect of disease of the liver on the 
body. 

The influence of liver disease on nutrition may in in- 
dividual instances depend on different causes. 

1. There may be partial or complete obstruction to the 
flow of bile leading to slight or intense jaundice. 

2. There may be damage to the liver cells, as in cirrhosis 
and atrophy. 

3. There may be obstruction to the portal circulation, 
interfering not only with the absorption of the digested food 
products, but also with the functions of the stomach, pancreas, 
and intestine. 

4. There may be coincident disease or disorder of the 
stomach and intestine associated either with a portal obstruc- 
tion or with the original cause of the liver disease, as in 
alcoholism. 



384 THE EFFECTS OF DISEASE OF THE LIVER 

Extirpation of the liver has been performed in geese 
after an Eck's fistula has been made, that is, after the portal 
vein has been joined to' the inferior vena cava, so that the 
portal blood is diverted from the liver into the systemic 
venous system. The animals lived from six to> twenty hours. 
A great change was observed in the urine, which, instead of 
containing, as normally, 60 to 70 per cent, of uric acid, was 
found to contain only from 2 to 3 per cent. The ammonia 
in combination was found to be increased to 60 per cent., the 
normal being from 9 to 18 per cent.; and lactic acid appeared 
in the urine. It is evident, therefore, that removing the liver 
from the body greatly disturbs proteid metabolism, in geese 
the normal transformation into uric acid of the products of 
this metabolism not taking place. In those diseases of the 
liver in which there is great destruction of the cells — as in 
cirrhosis and acute yellow atrophy — ammonia and lactic acid 
are found in the urine. 

After extirpation of the liver, it was found that the 
injection of arseniureted hydrogen, which in a normal animal 
causes jaundice, no longer produced this result, but caused 
hemoglobinuria. 

In dogs, when the liver is thrown out of action, as by the 
formation of an Eck's fistula, ammonium carbamate acts as 
a poison when injected into the circulation, owing to the fact 
that the liver does not transform it into urea. If the hepatic 
artery is ligatured, there is an increase in the blood of 
ammonium carbamate. The removal of the liver has also an 
effect upon the muscle-glycogen, causing a great diminution. 

The effect of great destruction of the liver is not seen in 
any disease except acute yellow atrophy, and also, perhaps, in 
the late stages of advanced cirrhosis. It is difficult to decide 
to what extent the symptoms of acute yellow atrophy are 
due to destruction of the liver substance, or to the action of- 
the poison producing the atrophy. The special liver symp- 
toms produced are confined to the appearance of jaundice; 
the vomiting, the nervous symptoms — such as a tendency to 
coma and delirium — the pyrexia, may all be ascribed to the 
action of a toxic agent on the tissues generally, and, for the 



EFFECT OF LIVER DESTRUCTION 385 

present, the subject must be left undecided at this stage. 
The initial experiments which have been done with hepato 
toxin are. however, of interest in this connection (p. 190), 
In acute yellow atrophy the main change is the profound 
destruction of the liver cells. The effect on nutrition is due 
not only to the liver disease, but to the greatly diminished 
quantity of food which is taken. The urea is greatly 
diminished — in some cases only traces having been found. 
The amount of nitrogen in the form of ammonia compounds 
is increased in proportion to the urea. Leucin and tyrosin 
are sometimes found in the urine, the latter even to the 
amount of 1.5 gram daily. The same bodies are found 
also in the liver substance and other tissues of the body. 
Their presence has been ascribed to the breaking down of 
the liver substance, but their formation is more reasonably 
ascribed to the action of bacteria. The uric acid, both in 
acute yellow atrophy and in phosphorus poisoning, is not 
appreciably diminished in quantity, and may be increased. 
Lactic acid is sometimes found in the urine, as well as albu- 
moses and aromatic oxy-acids (p. 403). 

Slow destruction of the liver substance occurs in cirrhosis 
and in carcinoma. In these cases, again, it is difficult to 
say how far the symptoms observed are due to a destruction 
of the liver substance, or to the action of some toxic agent. 
It may be said, however, that slowly progressing cirrhosis of 
the liver has a marked effect on the metabolism of the body, 
and may, of itself, produce death, even without the production 
of portal obstruction and ascites. Thus, wasting and bodily 
weakness ensue, which may be directly ascribed to the liver 
condition ; but whether the hemorrhages which occur, and 
sometimes the nervous symptoms, such as delirium and coma, 
are actually due to the liver disease, it is impossible, at present, 
to say. Pyrexia is observed in some cases of cirrhosis. The 
same difficulty in its explanation exists as with the symp- 
toms just discussed. It is present even when there is no 
obvious sign of infection, such as tuberculosis. The destruc- 
tion of the liver, which occurs in cirrhosis, undoubtedly 
predisposes to bacterial infection of one or other part of the 
25 



3 S6 THE EFFECTS OF DISEASE OF THE LIVER 

body, the disease tending to lessen the resistance of the 
body to infection. The liver being also a destroyer of 
poisons, the body is more readily affected by powerful drugs 
than in health. In cirrhosis of the liver there is damage 
to the liver cells, which are atrophied by pressure, and 
obstruction to the portal circulation. The effect on nutrition 
is dependent on these two factors, as well as on the diminished 
quantity of food and on the occurrence of hemorrhage and 
of diarrhea. There is, as a rule, a diminished excretion of 
nitrogen which appears to be chiefly due to the condition of 
partial inanition, although in some cases the nitrogen equilib- 
rium appears to be normal. Moreover, the nitrogen excreted, 
although for the most part existing in the form of urea, shows 
an increase in the amount of ammonia compounds which are 
present in the proportion of 8 to 12 per cent, to the total 
nitrogen excretion, as compared with 2 to 5 per cent., which 
is the normal amount. This increased excretion of nitrogen 
in the form of ammonia is at the expense of the amount of 
urea, and is no doubt to be ascribed to the inefficient trans- 
formation of ammonia compounds into urea by the liver cells, 
which are in part destroyed. The amount of uric acid is 
normal. The secretion of uric acid is not affected by liver 
disease, even the severest form, such as acute yellow atrophy. 
No leucin or tyrosin is found in the urine, and albumosuria 
does not occur. There is a considerable quantity of urobilin 
in the urine. 






CHAPTER XVI 

THE EFFECTS OF DISEASE OF THE KIDNEYS 

A Certain degree of functional activity of the kidneys is 
essential to life. This is due to the fact that the kidney excretes 
certain substances which are the products of nitrogenous metab- 
olism (such as urea and uric acid) or are the products of 
bacterial decomposition occurring in the intestine. The urine 
is the main channel for the excretion of the final products of 
nitrogenous metabolism, but these products are not of them- 
selves poisonous, and so it is not simply their retention in the 
body which leads to death after cessation of kidney function. 
The salts of potassium which occur in the urine are poisonous 
when administered in large doses either to the human being or 
to animals; but besides this, damage to the kidney has been 
shown to have a profound effect on the metabolism of the body 
in a manner as yet unexplained. 

If the excretion of urine is stopped death ensues, as is seen 
when double nephrectomy is performed, both ureters are 
ligatured, or, as in rare cases in man, when coagulation necrosis 
of the cortex results from thrombosis of both renal arteries. 
The results observed in complete cessation of the kidney func- 
tion show a series of symptoms which are fairly characteristic. 
Experimentally, there are no repeated vomiting, no convulsions, 
only occasional slight dyspnea and a fall of temperature, with 
wasting and muscular weakness. The duration of life is from 
three to five days in animals. In man, complete cessation of 
the renal functions is observed in cases of impaction of a 
calculus in both ureters : in the removal of one kidney or in the 
impaction of a calculus in the ureter, the other kidney having 

387 



3 88 THE EFFECTS OF DISEASE OF THE KIDNEYS 

been totally destroyed by disease ; and in the rare cases already 
mentioned of coagulation necrosis of the cortex. The duration 
of life in such cases is from seven to fourteen days, and the 
symptoms observed are mainly contraction of the pupils, mus- 
cular weakness, and a subnormal temperature. Sometimes 
there is severe vomiting, but there is no loss of consciousness, 
and no convulsions are seen. 

The urine itself is poisonous. In rabbits, 25-75 c. c. per kilo. 
of body-weight causes death. The toxicity varies in different 
diseases (Bouchard). The effects produced are convulsions or 
coma, with contraction of the pupils and failure of respiration, 
and have been ascribed to the poisonous action of the salts of 
the urine and certain unknown substances. The toxicity of the 
urine is said to be diminished in uremia. 

It is important to consider the effect of the partial loss of 
the kidney substance on the secretion of urine and on thegeneral 
metabolism of the body (Bradford). If part of one kidney is 
removed in a dog the only effect noted is an increase in the 
amount of water secreted, that is, polyuria. If, in addition to the 
first operation, the other kidney be removed, there is a persistent 
and great increase in the amount of water excreted, but nothing 
further is observed if the amount of kidney substance left is equal 
to one-third of the total kidney weight. The removal of three- 
quarters of the total kidney weight is fatal, and, besides the 
polyuria observed in the other experiments, the animal dies 
greatly wasted, showing a fall of temperature and occasionally 
diarrhea. There is a great accumulation of urea in the blood 
and tissues, and to the excretion of this the polyuria is directly 
due. Coma, convlusions, dyspnea, or vomiting are not observed, 
and there is no appreciable increase in the arterial blood pressure. 

The removal, therefore, of the greater proportion of the 
kidney substance leads to the accumulation of urea in the blood 
and tissues, and to' its increased formation, the loss of kidney 
substance having a profound effect on the proteid metabolism of 
the body. It has been suggested that this effect is due to* the 
absence, following destruction of the kidney substance, of some 
internal secretion. There is, however, no evidence of this, as in 
the case of the thyroid pituitary body, and the suprarenal 



DESTRUCTION OF THE KIDNEY SUBSTANCE 389 

bodies, and the great transformation of proteid into urea which 
occurs as the result of removal of three-quarters of the kidney 
substance is as yet unexplained. This removal does not 
reproduce the symptoms of uremia, as they are seen as the 
result of disease of the kidneys in man (p. 393). 

Destruction of the Kidney Substance in Disease. — The kid- 
ney substance is damaged to a greater or less extent in diseases 
of various origin. 

1. In Bright's disease, which may be divided into the acute; 
chronic parenchymatous, mixed fatty and fibroid, and the 
granular contracted kidney, the chief change is inflammatory. 
Into the various forms and degrees of these conditions it is not 
necessary here to enter, but to them generally belongs the fact 
that the stress of the disease falls on the cortex; the Malpighian 
bodies (the filtering apparatus) and the convoluted tubules (the 
secretory apparatus) being mainly affected, the blood vessels of 
the former being obliterated and the cells of the latter under- 
going degeneration. 

The extent of the damage in Bright's disease varies 
considerably, and is to be gauged by the extent to which 
the different parts mentioned are diseased. 

2. In lardaceous disease of the kidneys the small vessels 
of the cortex are mainly affected, more particularly in the 
Malpighian capsules. The convoluted tubules are secondarily 
affected, being either fattily degenerated or compressed by 
fibroid tissue. In the former case the degeneration is 
secondary partly to the neighboring lardaceous disease of 
the vessels, and partly to the disease producing the lardaceous 
disease, namely, suppuration, tuberculosis, or syphilis. 

3. Extensive caseous tuberculosis of both kidneys may 
occur, and so end life; so with double calculous pyelitis. 
Tumors are usually unilateral, especially when primary. 

In all these instances the pathological question to be 
considered is a partial damage to the kidney substance, the 
remainder of the kidney being practically normal and still 
capable of secreting. The effect of such disease from the 
point of view of damage to the kidney is to be gauged bv 



39 o THE EFFECTS OF DISEASE OF THE KIDNEYS 

the extent of damage, or rather by the amount of normal 
kidney substance remaining. In calculous pyelitis and in 
tuberculosis, in addition to the damage to the kidney there 
is the process of infection. 

4. Double hydronephrosis must be placed in a different 
category from the last group, inasmuch as in the case of 
Bright's disease the damage to the kidneys is general. 
Double hydronephrosis arises from pressure on both ureters 
in the pelvis or obstruction to the passage of urine from the 
bladder, either by enlargement of the prostate or by stricture 
of the urethra. It also occurs as the result of a new growth 
obstructing the orifice of both ureters and the bladder. 
Double hydronephrosis is incompatible with life. The obstruc- 
tion to the flow of urine, although not complete, leads to 
dilatation of the pelvis of the kidney, and to the pressure of 
the fluid on the kidney substance, which becomes anemic,, 
fibroid, and atrophied. 

Effects of Bright' s Disease on the Kidney Functions. — The 
effect of Bright's disease on the kidneys is to be discussed 
(1) as to the effect on the secretion of urine, (2) as to the 
effect on the circulation, and (3) as to the effect on the 
general metabolism. 

1. The effect on the urine in Bright's disease is observed 
not only in the amount of water secreted, but in the amount 
of the nitrogenous substances which are found in it. The 
amount of water varies considerably, and is to some extent 
in inverse proportion to the edema (p. 275). Circumstances, 
however, which more materially diminish the secretion of 
water, are the degree of congestion of the kidney substance, 
especially of the Malpighian capsules and the affection of the 
convoluted tubules. Thus a diminished amount of water is 
observed in acute and in chronic parenchymatous nephritis; 
while in the granular contracted kidney not only is the 
amount of water not diminished, but it is increased, diminish- 
ing only in the periods of subacute congestion which occur 
in this variety of kidney disease. It must be considered, 
therefore, that one of the chief conditions diminishing the 



THE CIRCULATION IN KIDNEY DISEASE 3gl 

quantity of water is congestion of the organ, and more 
particularly of the cortex. Blocking of the tubules by 
swollen cells acts only slightly in diminishing the urine. If, 
however, there is swelling of the cells over a large area of the 
kidney, as in some forms of acute and of chronic parenchymatous 
nephritis, the kidney becomes anemic from pressure on the blood 
vessels, and so less urine is secreted. This swelling of the 
kidney cells is an important fact in the pathology of the organ. 

2. The effect of kidney disease on the circulation, and the 
effect of the circulation on the secretion of urine, are of 
great importance. An increase in the quantity of urine is 
caused by an increase in the general blood pressure, which 
produces a rise of intracapillary pressure. This is caused by 
an increase of cardiac action, by contraction of the arterioles, 
or by the production of hydremic plethora, as in the drink- 
ing of large quantities of water. Relaxation of the renal 
arterioles also leads to an increased quantity of urine. The 
opposite conditions to the above lead to a decrease in the 
quantity. These physiological facts have a bearing on the 
amount of urine excreted in disease of the kidneys. In acute 
Bright's disease there may be a condition of increased arterial 
pressure produced by a contraction of the arterioles. This 
does not. however, lead to any increase in the amount of 
urine excreted in that disease, an increase being prevented 
by the permanent congestion of the organ, and thus the 
relative stagnation of the blood in it, as well as by the 
swelling of the cells of the convoluted tubules. The condition 
is not the same in the granular contracted kidney or in some 
forms of mixed fibroid and fatty kidney in which there is an, 
increased general arterial pressure with hypertrophy of the 
left ventricle of the heart, and an increased quantity of urine 
is excreted. The increased arterial pressure produces an 
increased flow of urine in this case because the organ is not 
so uniformly diseased nor swollen as in acute Bright's disease, 
so that the effect of the increased blood pressure can be exerted 
on the more or less normal parts of the kidney substance. 

An increased flow of urine is also observed, at any rate 
in the early stages, in lardaceous disease of the kidneys, and 



392 THE EFFECTS OF DISEASE OF THE KIDNEYS 

in this case the increased flow is more particularly to be 
ascribed to an increased permeability of the walls of the 
capillaries in the Malpighian bodies of the kidney which are 
affected by the lardaceous degeneration. 

The presence of an increased arterial blood pressure, when 
temporary, as in acute Bright's disease, or permanent, as in 
granular contracted kidney, whatever its mode of production, 
must be considered as in part a compensatory effort to' repair 
the damage to the organ. Its occurrence in acute Bright's 
disease is not yet explained, but inasmuch as it is sometimes 
temporary and is relieved or removed by bleeding, by purga- 
tives, or by the administration of nitrites, such as amyl nitrite 
and erythrol nitrate, it is plausibly attributed to> a generalized 
spasm of the arterioles produced perhaps by some poison 
circulating in the blood. 

In chronic granular contracted kidney, on the other hand, 
the long-continued high arterial pressure is associated 
with hypertrophy of the left ventricle and with a structural 
change in the arterioles in the form either of a fibrosis (arterio- 
capillary fibrosis), or of a spasm of the arterioles with or with- 
out hypertrophy of the muscular coat. The degree of arterial 
pressure in granular contracted kidney varies from time to 
time, and is reduced by the same means as in acute Bright's 
disease, though these means have a less effect than in the 
acute disease. It is probably correct to consider this increase 
of blood pressure as compensatory, inasmuch as it tends to 
increase the secretion of the kidney, the damage to> which 
tends to diminish the secretion. As has been stated, in acute 
Bright's disease this compensatory effort is not very effective 
in increasing the secretion ; whereas, in the granular contracted 
kidney, the compensatory effort on the part of the circulation 
produces, at any rate for long periods, an increased secretion. 

A certain degree of high arterial pressure is of service, 
and indeed a necessity, in chronic granular contracted kidney. 
The degree of arterial pressure varies from time to time. It 
is increased by an exacerbation in the disease of the kidneys, 
whether by an increase of the fibrosis or by the attacks of 
subacute congestion to which such kidneys are liable. It is 



UREMIA 393 

also increased by diseased conditions elsewhere in the body, 
such as the occurrence of a febrile disorder, of bronchitis, of 
constipation, or any form of intestinal intoxication. It is 
diminished and sometimes completely abolished, mainly by 
failure of the heart, whether by fibroid or fatty disease of the 
left ventricle, or degeneration of the muscular substance conse- 
quent on an infective disease. It is also diminished by profuse 
diarrhea or sweating. 

When the high arterial pressure diminishes and becomes 
subnormal, the amount of urine also diminishes. The amount 
of urine may also diminish with a continuance of the high 
arterial pressure, and this occurs when congestion of the 
organ supervenes, and at the onset of uremia. 

Uremia. — Uremia is a common termination of all forms 
of Bright's disease, whether acute, chronic parenchymatous, or 
fibroid, as well as of other diseases of the kidneys, in which 
both organs are affected. It must be distinguished from the 
results of complete (obstructive) suppression of the urine, which 
occurs in the human being from the impaction of a calculus in 
both ureters or from the removal of both kidneys, the results of 
which have been already described (p. 387). In true uremia 
the symptoms observed are referable partly to the digestive 
system, partly to the respiratory system, and partly to the 
nervous system, but all the effects are due to an action on the 
central nervous system. Uremia may occur with or without 
the signs of an increased arterial pressure. Persistent nausea, 
or vomiting, or diarrhea, is observed with or without dyspnea, 
and there are cramps, muscular twitchings or convulsions, with 
contracted pupils, delirium, maniacal attacks, paralysis, or coma. 
In individual instances one or other of these effects becomes 
prominent. Thus, repeated vomiting may be the chief sign in 
one instance, dyspnea in another, headache in another, twitch- 
ings or convulsions or contraction of the pupils, with rapid 
passage into delirium and coma in others. 

The explanation which has been offered of the occurrence of 
uremia is twofold : that it is due either to edema and anemia 
of the brain, or it is an intoxication affecting chiefly the central 



394 THE EFFECTS OF DISEASE OF THE KIDNEYS 

nervous system. It is difficult, however, to understand how 
edema or anemia of the brain can produce the prolonged 
irritative symptoms characteristic of many cases of uremia, 
and the condition appears more plausibly explained by the sup- 
position of an intoxication. What poison it is which produces 
the symptoms is not known. The retention of the urinary con- 
stituents in the tissues has been supposed to be the cause ; 
and Bouchard separated " urotoxins," which he stated were 
retained in the body in uremia. Urea, or any other of the 
nitrogenous bodies, does not produce, when injected, the symp- 
toms of uremia. It has been suggested that these nitrogenous 
bodies may by decomposition yield others of a more poisonous 
nature, such as ammonium carbamid. In this case the intoxi- 
cation may be due to retention of the urinary constituents in 
the body. It has also been considered that a new poison might 
be formed which would produce the symptoms, and some have 
described such a poison in the blood. Experimental evidence 
as to the cause of uremia is not as yet forthcoming. 

Changes in Metabolism in Kidney Disease. — The changes 
in nutrition which are observed in Bright's disease vary con- 
siderably, not only in individual cases, but in the various forms 
of the disease, and other factors than the disease of the organ 
have an important bearing on the changes that occur. The 
disease of the kidneys itself to a greater or less extent inter- 
feres with the excretion of the nitrogenous substances, and in 
some cases with the excretion of the amount of water. The 
presence of edema, as in acute Bright's disease and chronic 
parenchymatous nephritis, leads to other changes in nutrition. 
The changes in the circulation, either in the direction of in- 
creased arterial pressure, as in acute Bright's disease and 
granular contracted kidney ; or of diminished arterial pressure, 
as in some cases of chronic parenchymatous nephritis and the 
later stages of all forms, lead to further changes in the general 
nutrition. Anemia and loss of body-weight are the effects of 
the prolonged disease. 

Proteid Metabolism in Renal Disease. — A diminished 



METABOLISM IN KIDNEY DISEASE 395 

•quantity of food is taken in acute Bright's disease and in 
^some cases of chronic nephritis. The secretion of the gastric 
juice is not affected in the majority of uncomplicated cases 
of granular kidney, in which there is general well-being of 
the individual; but in acute and chronic parenchymatous 
nephritis there may be a great diminution in the amount of 
hydrochloric acid secreted by the stomach, leading to a 
diminished digestion of proteid food. The absorption of the 
food in the intestine is sometimes markedly affected in acute 
and chronic Bright's disease. It varies considerably, and may 
not differ from the normal, but in some cases the amount of 
nitrogen present in the feces is considerably greater than in the 
liealthy individual on the same diet. 

The metabolism of the nitrogenous constituents of the body 
varies considerably in individual cases and in the various forms 
of the disease. Three different classes may be recognized 
(Von Noorden). In one class the nitrogenous equilibrium is 
maintained; in a second class the nitrogenous excretion is less 
than the intake, so that there is a retention in the body (in the 
blood and tissues) of the final products of nitrogenous metab- 
olism. In a third class of cases more nitrogen is excreted 
than is taken in. The first class of cases includes those in 
which there is general well-being, in which the nitrogenous 
metabolism is not upset. The second class of cases includes 
those in which, owing to the extensive disease of the kidneys, 
elimination of the nitrogenous excretives is diminished, and so 
they are retained in the body. In the third class of cases 
the increased nitrogenous excretion is due either to resumption 
of the function of the kidney to a partial extent so that the 
retained nitrogen is excreted, or to increased breaking down 
of the nitrogenous tissues, or to both these events. 

It is thus seen that the commonly accepted statement that 
the nitrogenous excretion is diminished in Bright's disease is 
not to be taken unreservedly. The question must be considered 
not only in relation to the amount of food taken, but also to 
the amount of retention of nitrogenous excretives in the body. 
In acute nephritis, during the period of great diminution of 
urine, there is a deficiency of food taken, but the amount of 



396 THE EFFECTS OF DISEASE OF THE KIDNEYS 

nitrogen excreted with the urine is much less than that con- 
tained in the food. There is therefore nitrogenous retention, 
When improvement, however, occurs, the nitrogenous excre- 
tion increases — sometimes considerably — and this may be 
accounted for partly by the excretion of the retained products 
of nitrogenous metabolism, and partly by an increased activity 
on the part of the tissues. As an example, the following may 
be quoted (Von Noorden) : 

A child with scarlatinal nephritis received daily about 
8 grams of nitrogen in the food. At the commencement of 
the illness, that is, during the acute stage, the amount of 
nitrogen excreted on three days was found to be respectively 
3.2 grams, 6.5 grams, and 4.5 grams, that is, greatly less than 
the amount of nitrogen taken in as food. When improvement, 
however, occurred, the amount of nitrogen daily excreted was 
largely increased, being 14,2 grams and 16. 1 grams in two daily 
estimations. 

In chronic nephritis, in many instances the amount of 
nitrogen in the urine is greatly diminished, to the extent, it 
may be, of several grams daily. This applies more par- 
ticularly to cases of chronic parenchymatous nephritis and to 
advanced cases of granular contracted kidney. In some of 
the latter cases, however, the nitrogenous excretion may be 
greater than the nitrogenous intake. Thus, in a case of granu- 
lar contracted kidney in which 15.5 grams nitrogen were 
present in the daily diet, 20.1 grams nitrogen were found to be 
excreted. At a later period, however, in the same case, reten- 
tion of nitrogen occurred. Thus, on the same diet, during a 
period of five days, it was found that instead of excreting 75.5 
grams nitrogen to maintain the nitrogenous equilibrium, only 
53.18 grams were excreted, leaving 24.32 grams retained in 
the body. 

Retention of the Products of Nitrogenous Metabolism. — The 
retention of the products of nitrogenous metabolism which has 
been mentioned above refers almost solely to the retention of 
urea. In some cases uric acid may be retained, but not 
commonly; while creatinin, some amount of ammonia salts 



THE BLOOD IN KIDNEY DISEASE 397 

and of potassium salts, appear to be retained. Xanthin is fairly 
readily excreted, and ammonia salts are partly excreted and 
partly retained. The urea is increased in the blood. The 
normal amount obtained varies from o.oi to 0.05 per cent.; 
in Bright's disease, o. 1 to 0.3 per cent, may be found. In 
uremia the urea is in greatest amount, and may be as high as 
0.8 per cent. Urea is also found increased in the tissues and 
in the edema fluid, which may in some cases contain com- 
paratively large quantities. Thus in edema fluid 0.19 per cent, 
and 0.359 P er cent - nave been found. Retained urea, more 
particularly in cases of uremia, is sometimes found in the 
secretions of the body, most commonly in the saliva, and to a 
much less extent, in the gastric juice, the milk, and the sweat. 
The sweat may, however, contain an appreciable quantity 
of urea in cases of uremia. The presence of urea in these 
secretions is sometimes referred to as " the vicarious excretion 
of urea." Its presence is due, however, only to the passage 
of a highly soluble salt into the liquid which is given out from 
the mucous membrane or glands. 

The Blood in Bright 3 s Disease. — This shows great variation. 
In cases where there is well-marked edema the blood is in a 
hydremic condition (p. 275), and the specific gravity of the 
serum is diminished, being from 1020 to 1025 as compared 
with the normal of 1029 to 103 1. In the majority of cases 
no great change occurs in the corpuscles, but the red discs 
may be affected (p. 304). The alkalinity of the blood is 
greatly diminished, more particularly in uremia. 

The excretion of salts in the urine differs from the normal. 
There is a retention of potassium salts in the blood. The 
amount of chlorids in the urine is, as a rule, equal to the 
amount present in the food, but these are diminished when 
there is nitrogenous retention. The sulphates rise and fall 
with the amount of nitrogen excreted. This variation in the 
salts is to be ascribed to the renal condition. 

Changes in the Urine in Disease. — The composition of the 
urine is frequently a valuable index in disease. Not only does 



39« 



THE EFFECTS OF DISEASE OF THE KIDNEYS 



its composition show to an appreciably accurate extent the 
amount of proteid metabolism in health, but in disease as well 
there are substances present which are absent in health, such as 
blood, albumin, sugar, and fat, which are valuable guides in 
the estimation of disease processes. 

The normal amount of urine passed daily varies from 1200 
to 1700 c. c, about equal to 1 c. c. per kilo, of body- weight per 
hour. The specific gravity varies between 1015 and 1025, and 
depends on the amount of urinary solids. 



Composition of Urine : 

1. Nitrogenous Substances : 
Urea ..... CH 4 N a O 
Ammonia . . . NH 3 
Uric Acid . . . C 5 H 4 N 4 O s 

Hippuric Acid . . C n H 9 N0 3 
Creatinin . . . C 4 H 7 N 3 
Xanthin Bodies. 



Amount Daily Excreted : 



33 18 g- 

o.77 g., 

o.55 g-, 

too.75 g ., 

04 g- 
0.9 g- 

0.02t0.03g 



or 84 to 87 p. c. of total N. 
or 2 to 5 p. c of total N. 

) 



or 1 to 3 p. c. of total N. 



or 7 to 10 p. c. of total N. 



These nitrogenous bodies are not of the same significance 
from the point of view of disease. Whereas urea and the 
ammonium salts are derived solely from the proteid metabolism 
in the body, creatinin and hippuric acid depend on the kind of 
food taken, creatinin being derived from the creatin of flesh, 
while hippuric acid is derived mainly from vegetable food. 
Uric acid and the xanthin bodies may be grouped together, 
being partly derived from food and partly from proteid metab- 
olism, and mainly from the metabolism of nucleo-proteid. 
They have therefore an important bearing on conditions in 
which nucleo-proteid is set free in the body (p. 437). 



Mineral Salts : 




Daily 


Amount Passed 


Sulphuric Acid 


. . so 3 




2g- 


Phosphoric Acid . 


. . p 2 o 5 




3 5g- 


Chlorin. 






7 5g- 


Sodium. 






11.09 g. 


Potassium. 






2-5 g- 


Calcium. 






0.26 g. 


Magnesium. 






0.21 g. 



URINE IN DISEASE 399 

These salts, however, are not of equal significance. Some, 
such as chlorid of sodium and potassium, magnesium and 
•calcium phosphate, are taken in with the food. The sodium 
chlorid, however, differs from the phosphates in the fact that 
the amount excreted in the urine balances the amount taken 
with food; there is therefore a chlorin equilibrium in health. 
The phosphates are partly derived from food — more particu- 
larly vegetable food — but also are the result of proteid metab- 
olism, and mainly of nucleo-proteid and of lecithin. Sulphates, 
on the other hand, are not taken in with food, and result from 
proteid metabolism. Part of the sulphates appear as metallic 
salts, and part are combined with organic substances and 
appear as ethereal hydrogen sulphates (p. 403). The sulphates 
in urine have therefore a peculiar significance. The amount 
present is proportional to the proteid metabolism occurring in 
the body. 

3. Urinary pigments (p. 402). 

Composition of Urine in Disease. — It is evident that, in 
judging of the relation of the composition of urine to disease 
processes, there are several points requiring careful considera- 
tion. As regards nitrogenous substances, the amount of urea 
alone cannot be taken as a guide to the degree of proteid 
metabolism occurring in the body. All the nitrogenous con- 
stituents must be reckoned together. The total nitrogen in 
the urine does not, however, in disease or in health, give a 
correct indication of the amount of proteid metabolism, unless 
the amount of nitrogen in the food and that passed in the 
feces be estimated. If this is done, it is possible to determine, 
in a diseased condition, whether the nitrogenous equilibrium 
is maintained or not. The amount of urea present in the 
urine is an indication of a diseased condition only when it 
is greatly diminished or greatly increased. It is increased, 
for example, in pyrexia, which is the best example of an 
increased excretion of urea. There is, however, an increased 
formation of urea in many forms of renal disease, but, as in 
this case it is frequently retained in the body, the amount 



4 oo THE EFFECTS OF DISEASE OF THE KIDNEYS 

in the urine is no gauge of the proteid metabolism. In this 
case, therefore, there is increased formation of urea and 
diminished excretion. Greatly diminished formation of urea 
and diminished excretion occur more particularly in extensive 
destruction of the liver. A diminished quantity of urea in 
the urine, with an increased quantity of ammonium salts, 
especially when associated with the presence of lactic acid, 
indicates a diminished formation of urea by the liver. It there- 
fore occurs more particularly when the liver is diseased, and 
most markedly in cases of destruction of the liver cells as in 
acute yellow atrophy (p. 384). 

The amount of uric acid in the urine is not so> important 
an indication in disease as is sometimes thought. It is partly 
a product of proteid metabolism, and is greatly increased, as 
far as is known, in only one disease — leukemia. It is decreased 
in quantity in gout. Together with the other purin bodies it is 
increased by food containing nucleo-proteids, such as solid 
organs, sweetbread, thymus, liver, etc., taken as food (p. 437). 

Oxalic acid is present in the normal urine, to> the amount 
of 50 mgm., daily. It is mainly derived from the oxalates of 
vegetable food. It is increased in the urine when an excess of 
food containing oxalates is eaten, as well as in diabetes and in 
the obese. In diabetes, its increase is probably to be explained 
by an incomplete combustion of carbohydrates. Cystin, which 
is an amido-acid containing sulphur, may occur in certain 
individuals in excess, to the amount of 0.5 to 1 gram daily. 
Cystinuria occurs in families. 

While the sulphates and phosphates are increased by an 
increase in the proteid metabolism, the amount of chlorin in 
the urine is affected by the amount taken in the food, and in 
disease by the amount secreted in the gastric juice and by 
certain infective conditions. In the former case the amount of 
chlorin in the urine is increased, and in the latter case dimin- 
ished (p. 45). 

The amount of water daily excreted is sometimes greatly 
increased and sometimes diminished. It is increased in diabetes, 
mellitus, diabetes insipidus, in granular kidney, in the early 
stages of albuminoid kidney, and after certain nerve attacks 



AMOUNT OF URINE IN DISEASE 401 

(neuroses), such as those of migraine, epilepsy, hysteria, and 
asthma. The increase in the urinary water, in these cases, is 
not due to the same cause. Thus, in diabetes insipidus and in 
neuroses, it appears mainly to be dependent on a primary nerve 
condition, perhaps directly affecting the vaso-motor system 
of the renal vessels. In granular contracted kidney and in 
albuminoid kidney the kidney substance is destroyed, and the 
increased amount of urine is partly due to more ready filtration 
through the diseased vessels, and in granular contracted kid- 
ney is aided by the condition of high arterial pressure present. 
In diabetes mellitus the polyuria is dependent on the sugar 
present, which increases transudation through the renal ves- 
sels. The urinary water is diminished in many conditions 
of disease. Physiologically, the amount bears an inverse pro- 
portion to the amount of water given off in the perspiration. 
Thus the urinary water is diminished in profuse perspiration. 
A similar effect is observed in profuse sweating in disease 
as well as when there is profuse diarrhea, as in cholera and 
other acute intestinal conditions. A diminished quantity of 
urinary water is observed in pyrexia, and is in this condi- 
tion associated with a general diminution of the activity of 
the tissues. The diminished urinary water which occurs in 
acute nephritis and in chronic parenchymatous nephritis results 
directly from the disease of the renal tissue whereby the 
transudation of the liquid is hindered. Such a diminution 
may occur when the general blood pressure is increased or 
diminished. 

The specific gravity of the urine in disease varies within con- 
siderable limits from 1002 to 1050 or over. Very low specific 
gravity occurs in diabetes insipidus and after drinking large 
quantities of water, in both cases the proportion of urinary 
solids being low. A diminished specific gravity — 1008 to 
1012 — occurs in chronic Bright's disease, owing partly to the 
diminution in the proportion of urinary solids, and partly to 
the presence of albumin. An increase in the specific gravity 
of urine occurs in concentrated urines from whatever cause, 
as in pyrexia, profuse sweating, and diarrhea, and in certain 
intestinal conditions in which there is a large amount of unab- 
26 



4 02 THE EFFECTS OF DISEASE OF THE KIDNEYS 

sorbed liquid in the intestine. One of the main causes of 
increase in the specific gravity is the presence of glucose in the 
urine, as in diabetes. 

Pigments in the Urine. — The most abundant yellow pigment 
in the urine is uro chrome. It may be increased in disease, but 
this increase is of no particular pathological significance. 
Urobilin is another pigment, which exists in very small quan- 
tity in normal urine, probably as urobilinogen, which on expo- 
sure becomes oxidized to urobilin. Urobilin is one of the iron- 
free derivatives of hemoglobin, and is identical with the 
stercobilin of the feces. It is sometimes called normal uro- 
bilin as distinguished from pathological urobilin. Recent 
chemical research has, however, shown that the two bodies 
are probably identical. It closely resembles hydrobilirubin, 
which is a reduced product of bilirubin. Hydrobilirubin is 
said to contain more nitrogen than urobilin and to give a 
different spectrum. Urobilin is increased in the urine in 
different pathological conditions, and its source of origin is 
either bile or blood pigment. Thus, urobilinuria occurs in 
many cases of acute infective disease, as the result of large 
blood extravasations and of hemolysis, in pernicious anemia 
and in liver disease. It is also observed in acute and chronic 
alcoholism, and in the later stages of uncompensated valvular 
disease of the heart. 

Uroerythrin is a red pigment giving the color to the deposit 
of urates in the urine. Urohematoporphyrin is derived from 
blood pigment, and can be prepared by the action of reducing 
agents on hematin. It has been found in the urine in many 
different conditions, such as Addison's disease, cirrhosis of 
the liver, Hodgkin's disease ; and in infective processes, such 
as acute rheumatism, pneumonia, pericarditis, peritonitis, 
measles, meningitis, and typhoid fever ; as well as following the 
administrations of sulphonal. 

Melanin is found in urine in cases of melanotic sarcoma; 
the condition is called melanuria. Other pigments in the urine 
are derived from aromatic substances, which are discussed in 
the next section. 



AROMATIC SUBSTANCES IN URINE 403 

Aromatic Substances in the Urine. — These substances are 
present in normal urine, and are increased in certain patholog- 
ical conditions. The aromatic substances are derivatives of ben- 
zine, and are formed mainly by the action of putrefactive bac- 
teria on proteids. In the body they arise almost solely from 
putrefactive decomposition or other bacterial action in the intes- 
tinal tract, or from foul abscess cavities in the chest, as occurs 
in bronchiectasis and empyema. Formed in the intestine, 
they are absorbed into the tissues, and before being excreted 
in the urine, usually undergo some transformations. A 
few are excreted unchanged. Still fewer undergo some form 
of destruction in the body, while the majority are excreted in 
the urine in combination with sulphuric acid as ethereal hydro- 
gen sulphates. The amount of sulphuric acid, in combination 
with aromatic substances daily excreted in the urine, varies 
from 0.12 to 0.25 gram; over 0.3 gram daily being con- 
sidered abnormal. The proportion of ethereal hydrogen sul- 
phates to the total sulphates is as 1 to 12 or 15. The amount 
of aromatic substances in the urine is proportional to the 
extent of putrefactive processes in the intestine (Baumann). 
They are diminished in quantity in fasting dogs, especially 
if diarrhea be artificially produced; and also in human beings 
when diarrhea is produced by the administration of salts. 
The administration of so-called internal antiseptics appears 
to have no influence on the amount in the urine. The 
amount of these substances in the urine bears a direct rela- 
tion to the amount and character of the food taken. They 
are only formed from proteids. and thus with a large proteid 
diet imperfectly digested, they are increased in the urine. 
With a large carbohydrate diet the amount is diminished. 
In disease they are increased in all forms of putrefactive 
decomposition in the intestine, both with and without organic 
disease, as. for example, in cancer of the digestive tract. 
They are also increased in other forms of cancer, such as 
that of the uterus and mamma, the new growths becoming 
infected with micro-organisms. In diabetes, owing to the 
large amount of proteid food taken, they are increased even 
to the amount of 0.5 gram daily if the food is imperfectly 



4 o 4 THE EFFECTS OF DISEASE OF THE KIDNEYS 

digested and absorbed. If digestion is good, they are not 
appreciably increased. In severe anemias, such as pernicious 
anemia and leukemia, the amount of indican in the urine 
is increased; but in chlorosis, although in some cases an 
increase is observed, as a rule no such result occurs. The 
same irregularity in the increase is observed in jaundice, while 
the aromatic substances are diminished in inanition. 

The decomposition of proteid gives rise among other sub- 
stances to a series of bodies belonging to the aromatic group 
of organic bodies (p. 72). These may be classified as fol- 
lows : 

1. The Phenol Group, comprising tyrosin, aromatic oxy- 
acids, phenol, cresol ; and derivatives of these, such as phenyl- 
acetic acid and phenyl-propionic acid. 

2. The Indol Group, comprising indol, skatol, and deriva- 
tives of these. 

None of these bodies is formed in the normal metabolism 
of the tissues. Tyrosin is produced in pancreatic digestion, but 
all the bodies are the result of bacterial action. The substances 
to* be discussed are of some importance in disease, and belong to 
both groups of aromatic substances. Benzine is oxidized after 
absorption to a hydroxyl-derivative of phenol with the forma- 
tion of small quantities of pyrocatechin and of hydrochinon. 
The phenol compound combines with sulphuric acid, giving rise 
to a phenyl-sulphuric acid which is excreted in the urine in com- 
bination with sodium or potassium. In some cases the phenol 
combines with glycuronic acid and is so excreted. Traces 
of phenol (C 6 H B OH) and cresol (CH a C fi H 4 OH) are found in 
normal urine, about 0.003 gram daily. Pyrocatechin and 
hydrochinon (C 6 H 4 (OH) 2 ) are found in small quantities in the 
urine, the former giving a dark green coloration on exposure to 
the air. Pyrocatechin and hydrochinon are found in large quan-, 
tities in the urine in carboluria. Cresol is not infrequently 
oxidized in the body and excreted as cresyl-sulphuric acid. 

Other compounds of phenol found in the urine are aromatic 
carboxy-acids. Thus phenyl-propionic acid gives rise in the 
body to benzoic acid, which, uniting with glycocoll, forms hip- 



AROMATIC SUBSTANCES IN URINE 405 

puric acid, which is excreted in the urine. Another derivative 
is trihydroxy-phenyl-propionic acid(OH) 3 . C 6 H a C 3 H 4 . COOH : 
it is sometimes the cause of the darkening of the urine in 
" alcaptonuria." In this condition dihydroxy-phenyl-acetic 
acid has also been found, (OH) 2 C 6 H 2 . CH, . COOH, which is 
also called homogentisic acid. Alcaptonuria is a curious condi- 
tion resembling carboluria, in which the urine when alkaline 
becomes brown, first at the surface and then throughout, till 
it is nearly black. It is not associated with any special diseased 
condition, although it occurs in families. The color is due to 
the change in the aromatic substances in the urine produced by 
exposure to air. Some of the substances producing it may be 
derived from tyrosin. 

Indol and skatol differ from the preceding group in contain- 
ing nitrogen, and are excreted in combination with sulphuric 
acid. Indol is excreted as indoxyl-sulphuric acid in com- 
bination with potassium; this compound is called indican 
(C.H..NH .CH .C.KSO3). The daily amount varies from 
0.005 to 002 gram. Skatol is excreted as skatoxyl-sulphuric 
acid. Both bodies yield green, blue, and red pigments on 
oxidization. 

Blood and Bile in the Urine. — The presence of bile in the 
urine has already been discussed (p. 368), and that of blood 
partly (p. 325). With regard to blood all that remains to be 
said is that the presence of blood in the urine in the form of 
red corpuscles, white corpuscles, serum, and fibrils of fibrin 
occurs in disease of the genito-urinary tract of various forms — 
disease of the kidneys, lesions of the ureters, as by a stone, 
ulceration of the bladder and of the urethra. Hematuria may 
also occur from general disease, either during the excretion of 
poisons through the kidneys, as in phosphorus and cantharides 
poisoning, or as the result of the presence of free hemoglobin 
in the blood. In the latter case, the coloring matter may be 
either in the form of hemoglobin or of methemoglobin. 

Albuminuria. — The presence of albumin in the urine occurs 
in many different conditions. Physiological albuminuria is 



4 o6 THE EFFECTS OF DISEASE OF THE KIDNEYS 

described, but it is doubtful whether such a condition really 
exists. It is said to occur after prolonged muscular exercise, 
as in soldiers after a long march ; also from the application of 
cold to the body. It may be that in such cases there is a 
temporary congestion of the kidneys leading to a congestive 
albuminuria. What may be considered a true physiological 
albuminuria occurs after the taking of large quantities of egg 
albumin in some individuals, the albumin being in part excreted 
in the urine. 

The presence of albumin in the urine is in the great majority 
of cases a sign of disease, and may be ascribed to mainly three 
conditions : ( i ) An alteration in the circulation of the kidneys, 
mainly in the production of congestion — congestive albumi- 
nuria; (2) as the result of a toxemia — toxic albuminuria; and 
(3) disease of the kidney substance, as in Bright's disease — 
renal albuminuria. 

The form of proteid found in the urine in albuminuria is 
almost solely serum albumin. In some cases serum globulin 
is also found, and fibrinogen is present in cases of chyluria 
only. The amount of serum globulin is very small, and is 
said to be greater in those cases in which the urinary water 
is diminished, and in amyloid disease of the kidneys. The 
amount of albumin varies according to the condition produc- 
ing the disease. Thus it is usually slight in congestive and 
toxic albuminuria, while it is great in Bright's disease, in 
both the acute and chronic parenchymatous forms, and in 
amyloid kidney, but is small in granular contracted kidney. 
The amount of albumin present varies between 1 and 4 per 
cent. 

I. Congestive Albuminuria. — Albuminuria may be produced 
experimentally, by suddenly increasing the blood pressure in 
the kidneys, but mainly by the increase of the pressure in the 
renal veins ; ligature of the aorta below the kidney, and 
extirpation of one kidney; ligature of the aorta above the 
renal arteries; and compression of the trachea leading to 
asphyxia. Compression of the renal artery for a time, and 
re-establishment of the circulation, also leads to albuminuria, 



ALBUMINURIA 407 

probably by damaging the nutrition of the renal cells. In 
disease, congestive albuminuria is frequently noted, more par- 
ticularly in mitral disease with venous stasis, and in asphyxial 
conditions with an increase of the venous pressure throughout 
the body. 

2. Toxic Albuminuria. — This occurs in disease mainly in 
infective conditions. Albuminuria is a most constant sign in 
pneumonia, erysipelas, diphtheria, scarlet fever, and smallpox. 
It is not so common in typhoid fever, in measles, dysentery, 
or rheumatism. It is said to be common in malaria. In these 
conditions the albuminuria disappears two or three days after 
the cessation of the pyrexia. Globulin is frequently present 
with albumin in febrile albuminuria, and may be one half or 
more of the total proteid present. It is probable that febrile 
albuminuria is due to the excretion through the kidney sub- 
stance of bacterial toxins. Some of these, indeed, have a 
special action on the kidney substance, as shown in the pro- 
duction of cloudy swelling, seen more particularly in diphtheria 
and scarlet fever. Albuminuria may be due to the taking of 
poisonous chemical substances, such as cantharides, turpentine, 
and mercurial salts. In all these cases the condition is due to 
the direct action of the poisonous substance on the kidney. 

3. Albuminuria Due to Renal Disease. — The albuminuria 
present in Bright's disease is due to the damage both to the 
glomeruli and to the renal tubules, whereby a greater or less 
quantity of the albumin of the blood plasma escapes into the 
urine. In this case, however, besides the damage to the 
renal tubules, the condition of congestion of the organ leads 
to albuminuria. 

Several questions arise with regard to the effect of albumi- 
nuria in relation to Bright's disease. It is a loss of proteid 
to the body, and how far this loss is important has to be 
considered. Moreover, the effect of nitrogenous food on albu- 
minuria is an important point. The amount of albumin lost is 
greatest in acute Bright's disease and chronic parenchymatous 
nephritis, and in the acute exacerbations occurring in granular 
contracted kidney. In chronic parenchymatous nephritis the 
loss mav be considerable, and be extended over weeks or 



4 o8 THE EFFECTS OF DISEASE OF THE KIDNEYS 

months, but the amount lost varies considerably not only in 
individual cases, but from day to day, and at different periods 
of the day, even if the individual be on the same diet. In a case 
of parenchymatous nephritis, during twenty-four days 227 
grams of albumin were present in the urine, and thus lost to 
the body. This is equivalent to a loss of 9.4 grams daily (Von 
Noorden and Ritter). This patient, however, was in a condi- 
tion of nitrogenous equilibrium, owing to the large amount of 
proteid of the food which was absorbed. The patient received 
97 grams of proteid a day, 87 grams of which were utilized 
by the body. The loss of albumin in this case, therefore, was 
not felt by the individual. If, however, the food is deficient in 
proteids the loss of albumin in the urine may be serious 
from the nutritional point of view. 

Albumosuria. — Albumosuria, or peptonuria as it is some- 
times called, is a condition quite distinct from albuminuria. 
Albumoses are sometimes found in the albuminous urine of 
Bright's disease ; they are not, however, excreted by the kidney, 
but formed in the urine in the bladder or when passed. The 
amount of albumoses present in such cases increases in the urine 
on standing, and their presence is due to the action of the pepsin 
in the urine. The albumoses found in urine are either hetero- 
albumose ( Bence- Jones' albumin) or deutero-albumose. As a 
rule they are present in solution, but in some cases they form 
part of the deposit in the urine. Hetero-albumose is precipi- 
tated at a temperature between 43 and 50° C, and is also 
precipitated by acid, the precipitate redissolving on heating. 
This form of albumin has been found almost solely in osteo- 
malacia, and appears to result from the breaking down of the 
new cells in that condition. Most forms of albumosuria are 
due to the presence of deutero-albumose : in some cases proto- 
albumose has been found. In some cases it is supposed that the 
albumoses formed in peptic and pancreatic digestion do not 
completely undergo transformation into the proteids of the body 
during their absorption, and are thus partly excreted in the 
urine. Hetero- and proto-albumoses injected into the body 
pass out in the urine mainly as deutero-albumose. Deutero- 
albumose, when injected, passes out mainly as peptone, while 



ALBUMOSURIA 409 

peptone is excreted unchanged. Albumosuria is as a rule 
a condition met with in infective processes, such as collections 
of pus, more particularly empyema, purulent bronchitis, tuber- 
culosis of the lungs and lymph glands, and extensive ulcera- 
tion of the skin and intestine. Albumoses are present in pus, 
and no doubt are the source of those found in the urine. The 
condition is present when no abscess is formed, as in some cases 
•of pneumonia, septicemia, typhoid fever, measles, and scarlet 
fever, and it is probable that in these cases the albumoses 
formed by the infective agent are those which are present in 
the urine. Albumosuria is also present sometimes after par- 
turition, in which case it is ascribed to rapid involution of the 
uterus. In phosphorus poisoning it has been noted. Albumo- 
suria is mainly associated therefore with some toxic condition, 
and is, in the majority of instances, due to the formation of 
the substances in the tissues and their subsequent excretion in 
the urine. 



CHAPTER XVII 

THE EFFECT OF DISEASE OF THE DUCTLESS GLANDS 
ON THE BODY 

The organs of the body comprise those — such as the heart 
and lungs — which have to do with the circulation and 
aeration of the blood; those concerned in the neuro-muscular 
system; and those concerned in the digestion and elaboration 
of the food taken into the body, such as the salivary glands, 
pancreas, liver, and the glands of the mucous membrane of 
the gastro-intestinal tract. Connected with excretion are the 
kidneys and glands of the skin, and with generation are the 
ovary and testis. Besides these, with their specialized func- 
tions, there are certain ductless glands, the functions of which 
have been until lately very obscure. These are the thyroid, 
the thymus, the pituitary body, the suprarenal capsules, the 
spleen, and the coccygeal and carotid glands. 

The thyroid, thymus, and pituitary body are primarily 
formed by the invasion of the stomodeum (ectoderm) in the 
embryo, the duct being obliterated. The suprarenal capsules 
are formed in connection with the Wolffian body, and consist 
of mesoblast. The spleen consists of mesoblast, which is also 
represented in the thymus and in the pituitary body. 

The knowledge that a gland without a duct is of importance 
in the healthy body is the result of recent investigations into 
the effect on the body of the removal of the ductless glands. 
This effect varies with each gland, and has demonstrated the 
fact that some of the glands are essential to life. These are 
the thyroid, the pituitary body, and the suprarenal bodies; 
while removal of the spleen or thymus does not endanger life. 

410 



THYROID GLAND 41 1 

The removal of the thyroid induces a diseased condition 
in the body, which is the counterpart of the disease which 
occurs naturally — myxedema. The removal of the pituitary 
body leads to definite symptoms in animals; while the result 
of the removal of the suprarenal bodies is to a great extent 
the symptoms which occur naturally in Addison's disease. 

The effects of removal of the liver have already been 
discussed (p. 384). The presence of the liver is essential to 
life, and its removal has a profound effect on the chemical 
changes in the body. The effect of removal of the kidneys 
is discussed in Chapter XVI. The loss of a certain proportion 
of the kidney substance has also a profound effect on the 
nutritional or metabolic changes which occur in the body. 

The salivary glands, as well as the mammary glands, may 
be removed without the production of symptoms; but the 
removal of the pancreas, a gland whose main function is 
apparently the secretion of a digestive juice acting on proteids 
and carbohydrates, leads to disease and the production of 
glycosuria — that is. to an effect on metabolism (p. 444). 

The changes resulting from the removal or disease of the 
thyroid, the pituitary body, and the suprarenal capsules, are 
partly due to a changed metabolism of the body, but are also 
shown in a profound effect on the nervous system, and in 
some cases on the circulation. 

The Thyroid Gland. — The diseases which have to be dis- 
cussed in relation to the thyroid gland are on the one hand 
myxedema, cretinism, and cachexia strumipriva; and on the 
other hand, exophthalmic goiter (Graves' or Basedow's 
disease). The three first diseases show the same pathological 
changes, myxedema being the natural disease in adults, 
cretinism the same disease in infants or children, and cachexia 
strumipriva. a similar condition which supervenes in man as 
the result of the total removal of the thyroid gland. In 
most of the symptoms myxedema is in strong contrast with 
exophthalmic goiter. Thus, in myxedema, there is an increase 
in the size of the body, a dry skin, apathy leading to stupor, 
tremor, a low body temperature with a low blood pressure 



4 i2 EFFECT OF DISEASE OF THE DUCTLESS GLANDS 

and slow pulse due to a diminished cardiac action, and an. 
atrophied thyroid: while in exophthalmic goiter there is 
wasting, nervous or even maniacal excitability, tremor, an in- 
creased blood pressure and rapid action of the heart, with a nor- 
mal temperature (sometimes pyrexia) and an enlarged thyroid. 
Myxedema occurs more commonly in women than in men 
in a proportion of about six to one, and is accompanied by 
certain anatomical changes. The thyroid shows extensive 
fibrosis of the gland, which succeeds a round-celled infiltra- 
tion. There is at first a proliferation of the cells of the 
alveoli, ending in degeneration and complete loss. The gland 
greatly diminishes in size, and is the chief part affected 
in myxedema. The increase in size of the patient, which was 
at one time considered as due to mucin, is due mainly to an 
increase of fat. There is thickening in the skin round the 
hair follicles and the sebaceous and sudoriferous glands, which 
has been considered as probably inflammatory (Virchow). 
Associated with these anatomical changes, interstitial nephritis 
with a hypertrophied left ventricle is present in about one- 
third of the cases, and petechial hemorrhages are sometimes 
found in the medulla oblongata. The gross face and body, 
spade-like hands, the gruff voice, slow speech, and general 
apathy, with the thinning of the hair and slow pulse, are 
characteristic of the developed disease in man. The disease 
was first described by Gull (1874), and in 1878 was connected 
with disease of the thyroid (Ord). Previously it had been 
shown that extirpation of the thyroid in dogs was fatal 
(Scruff, 1856), and it was found that complete extirpation of 
the thyroid in man for goiter was followed by symptoms 
which were proved to be characteristic of myxedema 
(Kocher). The disease in many of its aspects is also repro- 
duced in dogs and monkeys by the removal of the thyroid, and 
it was found that the deleterious effects were prevented by a 
previous and successful grafting of a portion of healthy thy- 
roid in the abdominal cavity of the animal (Schiff). No 
results follow the extirpation of the gland in birds, and the 
results in rabbits are frequently negative unless the accessory 
thyroids and parathyroids are removed. 



MYXEDEMA 413 

Experimental Myxedema. — After removal of the thyroid, 
the symptoms in animals commence at about the fifth day 
(from the second to the twelfth day). They commence earlier 
in young animals, and when the animal is exposed to cold. 
A sheep, for example, in which the gland was removed, lived 
for two years without symptoms; myxedema, however, 
developed when the animal was sheared. 

The symptoms which are observed in a myxedematous 
animal may be classified as follows : Affections of motility 
are shown in the development of tremor, of clonic spasms, 
sometimes of contracture, the onset of paresis and sometimes 
of paralysis. An affection of sensation is shown in the de- 
velopment of paresthesia, which is followed by anesthesia, 
while the reflexes are greatly diminished. Mental operations 
are affected, being slowly performed, and there are apathy and 
lethargy which may lead to coma. The body temperature, 
which may be raised and irregular at first, gradually falls and 
becomes subnormal. The appetite — voracious at first — fails, 
and may be lost (anorexia). There is a diminished blood 
pressure with gradually increasing anemia and leukocytosis. 
An effect on the general nutrition is shown by a mucinous de- 
generation of the connective tissue and an increase of mucous 
secretion from the membranes. The spleen is sometimes en- 
larged, and usually there are atrophy and falling out of the hair. 

Not only, then, is nutrition affected as the result of the loss 
of the thyroid, but there is a profound effect on the central 
nervous system and on the circulation of the blood. It has, 
moreover, been found that in animals without a thyroid the 
respiratory exchange is disordered, as when exposed to cold 
such animals show an immediate increase in the amount of 
carbonic acid given off, there being no delay, as in the case of 
the normal animal. 

The diseased condition produced by removal of the thyroid 
gland is prevented ( 1 ) by grafting a portion of healthy thyroid 
into the animal before the operation, (2) by injecting a watery 
extract of the gland into the animal after the operation, or (3) 
by feeding the animal with the gland. Similarly, it has been 
shown that in the natural disease (myxedema) occurring in 



4 i4 EFFECT OF DISEASE OF THE DUCTLESS GLANDS 

man, the symptoms completely disappear when an extract of 
the gland is either repeatedly injected under the skin or given 
continuously by the mouth. Extirpation or disease of the 
gland, therefore, removes something from the body which is 
essential to health and to life, the absence of this substance 
leading to a definite train of disease symptoms. 

The Action of Thyroid Extract. — The active principle of the 
thyroid gland has a definite physiological action which is not 




p IG 107.— Effect upon the blood pressure in the dog of *the in- 
travenous injection ot uecoction of thyroid. 

Time in seconds. The line above the time tracing is the abscissa of 
the mercurial manometer. (Schafer.) 

destroyed by drying at a low temperature or mixing with water. 
Attempts which have been made to isolate the active principle 
have not been successful. It is regarded by some as a proteid. 
A crystalline substance, thyreo-anti toxin (C„H n N a OJ (Fraen- 
kel) has been described, as well as a body called iodothyrin, 
which consists of a proteid in combination with a large 
quantity of iodin. The exact nature of the active principle is, 
however, still unknown. It produces its effects in very small 
doses, and has a profound effect not only on the vascular 



ACTION OF THYROID EXTRACT 415 

system, but on metabolism. Injected intravenously in an ani- 
mal, the watery extract of the thyroid gland causes a well- 
marked fall of blood pressure (Fig. 107), due not to any alter- 
ation in the rate or strength of the cardiac beat, but to a dilata- 
tion of the peripheral blood vessels. In animals it has been 
found that thyroid feeding at first increases the execretion of 
nitrogen, but that this soon passes off, and nitrogen aquilib- 
rium is regained. In the healthy but obese human being, thy- 
roid extract, when given by the mouth, produces a loss of 
weight due to the diminution in fat. It therefore increases 
metabolism in the body. It may produce a temporary glyco- 
suria and an increase in the amount of urea excreted, espe- 
cially when given in large doses. In such cases, too, an in- 
creased frequency of the cardiac beat is observed. 

The most marked effect, however, of the action of the 
thyroid extract is observed in cases of myxedema and in 
cretinism. The regular administration of thyroid extract in 
myxedema leads to the following results : 

1. There is a great diminution in body-weight, which may 
be as much as a loss of three stone in two or three months. 
This loss of body- weight is accompanied by the disappearance 
of the coarse features and husky voice. 

2. There is a disappearance of the nervous symptoms, the 
tremor, and the mental apathy. 

3. Other nutritional changes are observed in the rise of 
body temperature, in the skin becoming moist, and in the 
growth of the hair. 

4. The effect on the circulation is observed by the slowed 
pulse becoming more frequent. A greatly increased frequency 
of the cardiac beat (120 to 140) may result from the action 
of thyroid extract in myxedema. 

The continued administration of the extract leads to a 
return to the normal condition; that is, all the effects of the 
loss of the thyroid gland disappear. For the maintenance, 
however, of the individual in this normal condition, the ex- 
tract of gland has to be given continuously. It supplies some- 
thing to the body which comes normally from the thyroid 
gland, and the loss of which by disease of the gland leads to the 
profound disturbances observed in myxedema. 



4 i6 EFFECT OF DISEASE OF THE DUCTLESS GLANDS 

The pathological relation of myxedema to exophthalmic 
goiter is one of great importance. The symptoms have already 
been contrasted. In both conditions the thyroid gland is af- 
fected — atrophied in myxedema, enlarged in exophthalmic 
goiter. The enlargement of the thyroid gland is partly due to 
an increase in the size of the vessels which are sometimes hy- 
pertrophied, but mainly to the great increase of the secreting 
structure. The epithelium of the vesicles shows great prolifer- 
ation, and the colloid secretion is more copious, and there is 
evidence of the formation of new vesicles. These anatomical 
changes are signs of an increased activity on the part of the 
gland, and are to be considered with the symptoms of the dis- 
ease. Thus the increased frequency of the cardiac beat (tachy- 
cardia), the nervous excitability, and the emaciation, are in di- 
rect contrast with the slow cardiac beat, the nervous apathy, 
-and the grossness of body in myxedema, and might indeed be 
taken to represent the action of large doses of thyroid extract; 
and it must be considered a plausible conclusion that the symp- 
toms of exophthalmic goiter mentioned above are due to the 
presence in the blood and tissues of an excessive amount of the 
active principle of the thyroid gland. The disease exophthal- 
mic goiter cannot be produced in healthy animals by the injec- 
tion of thyroid extract. This, however, is not a final argument 
against the view stated above. Whatever may be the fate of 
the active principle of the thyroid gland in the healthy body — 
and as to the details of this no knowledge is at present forth- 
coming — it is probable that, as in other instances, the tissues 
can act on the defensive against an excess of so powerful a sub- 
stance; that is, the excess of the substance is destroyed in the 
body, and this may be the case in attempts to reproduce ex- 
ophthalmic goiter experimentally in healthy animals. There is 
probably in exophthalmic goiter some other factor than the in- 
creased secretory activity of the thyroid gland, and possibly this < 
is to be attributed to an affection of the nervous system. In 
many cases of the disease the thymus gland is enlarged and 
persistent, but the relation of this condition to the disease is 
unexplained, and the administration of thymus extract has no 
appreciable effect on the course of the disease. The influence of 



THE PITUITARY BODY 417 

nervous shock in initiating exophthalmic goiter is an important 
fact, and the disease has been ascribed to an affection of the 
sympathetic nerves or to a disorder of the central nervous sys- 
tem, more particularly of the centers in the medulla. It has 
not as yet been shown that the central nervous system regulates 
the activity of the thyroid gland, but it may be that a change 
in the nerve center initiates the excessive activity of the gland 
which is observed in exophthalmic goiter, as indeed it might 
be supposed to initiate the diminished activity leading to 
atrophy which occurs in myxedema. 

The Pituitary Body. — The disease which has to be con- 
sidered in relation to the pituitary body is acromegaly, in 
which there is evidence of a disordered nutrition as well as an 
effect on the circulation. There is an enlargement of the face 
and of the extremities due mainly to a thickening of the bones, 
which is practically an exaggeration of the normal prominences 
of the different bones. With this is associated some thickening 
of the integuments. The face becomes coarse, and the hands 
and feet become gigantic. The back is bowed, and the whole 
condition may be associated with great muscular strength, al- 
though in the latter stages of the disease there is great muscu- 
lar weakness. Thickening of the arteries has been described, 
and the pulse may be weak. Acromegaly is associated in many 
cases with an enlargement of the pituitary body, which is some- 
times due to hypertrophy and sometimes due to the presence of 
a new growth. The disease is also sometimes associated with 
enlargement of the thyroid gland. Although the relation of 
acromegaly to the condition of the pituitary body is not yet 
definitely settled, yet the investigation of the functions of the 
pituitary body has led to the discovery that its integrity is es- 
sential to life. The anterior lobe of the pituitary body, which 
is derived during development from the epiblast, differs from 
the posterior lobe, which consists of nerve tissue. The struc- 
ture of the anterior lobe is somewhat like that of the thyroid, 
consisting of roughly spherical alveoli which contain a semi- 
fluid substance as well as nucleated cells. 

Removal of the pituitary body in cats (Marinesco) and in 



4 iS EFFECT OF DISEASE OF THE DUCTLESS GLANDS 




THE SUPRARENAL BODIES 419 

dogs (Vassali and Sacchi) leads to death within fourteen 
days. The symptoms observed are a diminution of body tem- 
perature, anorexia, lassitude, muscular twitchings, tremors, and 
spasms and dyspnea. The symptoms therefore show not only 
an effect on the nervous system, but an effect on metabolism. 
To some extent the pituitary body appears in its functions to 
have some connection with the thyroid. Not only, as has 
been stated, is the thyroid sometimes enlarged in acromegaly, 
but in some cases following thyroidectomy the pituitary body 
has been described enlarged, although in myxedema this is 
not generally the case. An extract of the pituitary body, 
however, has a different physiological action from that of ex- 
tract of the thyroid gland; for whereas the extract of thyroid 
produces a fall of blood pressure without any appreciable 
effect on the cardiac beat, extract of pituitary body causes a 
well-marked rise of blood pressure, with an augmentation of 
the heart beat (Fig. 108). Moreover, extract of pituitary body 
appears to have a direct action on the blood vessels causing 
their contraction. In both these respects it resembles supra- 
renal extract. 

The Suprarenal Bodies. — Disease of the suprarenal bodies 
is observed in Addison's disease (Addison, 1855). This dis- 
ease is characterized by a definite association of symptoms; 
such as great muscular weakness, a very feeble pulse and circu- 
lation, vomiting and pigmentation of the skin and mucous 
membrane of the mouth. These symptoms occur without any 
definite affection of the nervous system, such as paralysis of 
motion or sensation, or alteration of the special senses or of the 
mind. Indeed, Addison's disease in its progressive stages 
presents the features of an intoxication without pyrexia; the 
low body temperature, the profound weakness, and the ex- 
tremely feeble circulation recalling symptoms which occur after 
the pyrexial stage of a known infection, such as typhoid fever, 
or like the apyrexial toxemia of diphtheria. 

The pigmentation occurs in the parts most exposed to 
pressure, and is due to an increase in the normal pigment of 
the part when it occurs in the skin. In the mucous membrane 



420 



EFFECT OF DISEASE OF THE DUCTLESS GLANDS 



of the mouth and tongue, although usually most marked where 
the parts are pressed upon by the teeth, it may be that the 
pigment is formed from the blood more directly than in the 
case of the skin. The suprarenal capsules may either wholly 
or in part be destroyed by atrophy, fibrosis, calcareo-caseous 
degeneration (tubercle), or by tumor. Of these the lesion 
most common in Addison's disease is calcareo-caseous degen- 
eration, in which at death the original structure of the capsules 
is found destroyed. 

Removal of the suprarenal bodies is fatal (Brown-Sequard. 





Fig. 109. — Effect of suprarenal extract upon muscle contraction in 

the frog. 

A, Normal muscle curve of gastrocnemius; B, curve taken during suprarenal 
poisoning, but otherwise under the same conditions as A. Time tracing, 100 per 
second. (Schafer.) 

1856), and the symptoms described as following the opera- 
tion are: great muscular weakness, weak circulation, and 
loss of appetite. Although Brown-Sequard did not observe 
pigmentation in his experimental animals, this has been 
said to occur in the slow experimental destruction of the 
capsules, as when they are inoculated with a micro- 
organism (the pseudo-tubercle bacillus). For the effects to 
be produced both capsules must be removed. The blood of 
animals dying after removal of the capsules is poisonous, not 
to normal animals, but to other animals in which extirpation 
of the capsules has just been performed, a statement which 
is not at present explained by the further work that has 



ACTION OF SUPRARENAL EXTRACT 421 

been done on the suprarenal capsules. The toxicity of the 
blood of such animals has given rise to the idea that the 
function of the suprarenal capsules is to remove some poison 
from the system which accumulates when the capsules are 
taken away. This statement has no apparent connection with 
the physiological action of the extract of the gland. 

Physiological Action of Extract of Suprarenal Capsules. — 
An extract of the cortex does not contain any active principle, 
but an extract of the medulla contains a toxic substance not yet 
isolated. This substance is soluble in water, and is not de- 
stroyed by boiling for a short time. It has the following phys- 
iological action (Schafer and Oliver) : Large doses of the ex- 
tract cause an acceleration and increase of the cardiac beat, 
with shallow and rapid respiration and a fall of temperature. 
Rabbits are more susceptible than guinea-pigs, dogs, or cats. 
In certain doses the injection of the extract appeared to 
confer immunity against a subsequent fatal dose. 

The extract has a definite effect on voluntary muscle (Fig. 
109), the contraction of which it enormously prolongs, like the 
alkaloid veratrin. In the heart, when the vagi are uncut, it 
causes a slowing or stoppage of the beat. With the vagi cut, 
the auricular contraction is augmented as well as that of the 
ventricle. Suprarenal extract causes an enormous rise of blood 
pressure (Fig. no), due to contraction of the arterioles, as 
shown not only by a blood pressure tracing, but by means of 
the plethy sinograph. This effect passes off in a few minutes, 
but during its continuance, owing to the firm contraction of 
the arteries, a stimulation of the depressor nerve has no 
effect in lowering the blood pressure. The extract acts 
locally when applied to the blood vessels, and not through 
stimulation of the vaso-motor center. A corresponding 
organ which exists in certain fishes (elasmobranchs) yields an 
extract similar in action to that of the capsule of the higher 
vertebrates already described, so that it appears that this 
substance which has such a powerful physiological action is 
associated with the functional activity of the suprarenal body. 
It acts in extremely small doses, and a distinct physiological 



ACTION OF SUPRARENAL EXTRACT 423 

effect on the heart and arteries may be obtained by the 
administration in the dog of as little as one millionth part 
of a gram per kilo, of body-weight (Schafer). The repeated 
subcutaneous injection of suprarenal extract in the form of 
adrenalin chlorid solution (1 in 1000) leads to glycosuria, 
like the injection of phloridzin (p. 442). It also leads to an 
increased nitrogenous excretion. 

In Addison's disease, as far as can at present be stated, 
the destruction of the function of the suprarenal capsules 
removes from the body a substance which has the effect of 
causing a rise in blood pressure as well as an increase of the 
muscular contraction, and it is the loss of this body which 
appears to lead to great muscular weakness as well as to weak- 
ness of the circulation. The administration of supra- 
renal capsule extract in Addison's disease is said to be at- 
tended with useful, but not curative results. The extract has 
been used for the stoppage of both local and internal hemor- 
rhage, the rationale of this treatment being the local effect 
of the extract on the arterioles. 



CHAPTER XVIII 



CHANGES IN METABOLISM 



In the normal individual nutrition is maintained by the food 
eaten and the oxygen respired, as well as by the passage in 
the excreta of the products of metabolism of the tissues. The 
amount of food required varies in different conditions. It must 
consist of proteid, fat, carbohydrates, salts, and water in certain 
proportions. The proteid supplies the nitrogenous food nec- 
essary for the tissues, while the fat and carbohydrates are the 
sources of heat and energy. Nitrogen in the form of urea and 
uric acid is excreted in the urine and in an unmetabolised form 
in the feces. The combustion of fat and carbohydrates in the 
body gives rise to the formation of carbonic acid, which is 
discharged mainly by the lungs, and of water. The following 
table (Ranke), quoted in Halliburton's Physiology, is a table of 
exchange on a definite diet : 



EXCHANGE OF 


MATERIAL ON AN ADEQUATE DIET. 


Foods. 


Income. 


Expenditure. 


Calories. 


Nitrogen 


Carbon 


Excretions. 


Nitrogen 


Carbon. 


Proteid, ioo gr. 

Fat, ioo gr. . 

Carbohydrates, 
250 gr. 


410 

930 

IO25 


Grams. 
I5o 


Grams. 
53-0 

790 

93-0 


Urea, 31.5 gr. ) 
Uric Acid, 0.5 ) 
Feces .... 
Respiration(C0 2 ) 


Grams. 
14.4 

I.I 
O.O 


Grams. 
616 

10.84 
208 . 00 




23^5 


15-5 


225.0 




15.5 


225.OO 



424 



PROTEID METABOLISM 425 

The heat value of this diet is 2365 calories. This is rather 
below the average diet required, which ought to be about 3000 
calories, as in Voit's diet, consisting of 105 grams of proteid, 
56 grams of fat, 500 grams of carbohydrates. In man, the 
least amount of nitrogen which is to be taken in with the food 
is 15 grams, which is contained in about 100 grams of proteid. 
If the food contains smaller quantities of nitrogen the tissues 
utilize their own nitrogen for metabolism and the body wastes. 
If the amount of proteid food containing nitrogen is increased, 
the excretion of nitrogen is also increased, and in all cases in 
health a condition of nitrogen equilibrium becomes established, 
in which the output of nitrogen is equal to the intake in the 
food. 

Fats and carbohydrates permit of a smaller quantity of nitrog- 
enous food being taken than would otherwise be necessary, so 
that they are considered as proteid sparers in the diet. For 
details on this and other points, works on physiology must be 
consulted. It is necessary, however, to consider certain points 
in relation to the constituents of food which have an important 
bearing on nutrition in disease. 

Proteid Metabolism. — The character of the nitrogenous sub- 
stances taken in as food is not a matter of indifference to the 
body. The proteid foods which serve to maintain the nitrog- 
enous equilibrium are such as those contained in muscle, milk, 
eggs, and in cereals and leguminous seeds. These may be 
referred to as native proteids. They undergo the process of 
digestion in the stomach and small intestine by the gastric and 
pancreatic juices. Thereby they are rendered more soluble, 
being transformed into albumoses. These products of digestion 
are retransformed during their absorption by the mucous mem- 
brane of the intestine into the proteids of the body, albumoses 
as such not being present in the normal tissues. Proteids are 
therefore not directly assimilated by the tissues, and many of 
them when injected into the circulation are excreted in the 
urine, such, for example, as egg-albumin and albumoses. 

Gelatin, which is a nitrogenous substance and undergoes a 
process of digestion in the stomach with the formation of bodies 



426 CHANGES IN METABOLISM 

allied to albumoses, is not a substitute for proteids in the diet, 
and, from a dietetic point of view, is to be considered simply as 
a proteid sparer, and as such is to be placed in the same class 
as fats and carbohydrates. 

Nucleins and nucleo-proteids are constantly present in foods, 
and these bodies have some relation to the amount of uric acid 
in the urine, and of other bodies of the purin class. 

The metabolism of proteids in the body is associated with 
the activity of the tissues, for although muscular work does not 
increase the amount of nitrogenous excretion, yet the urea and 
uric acid present in the urine are derived from the breaking 
down of the nitrogenous substances in the body. Urea 
(CON 2 H 4 ) is not a direct derivative of tissue metabolism. It 
is not, for example, formed in the muscles which constitute a 
large part of the body and are constantly in activity. It is 
formed in the liver, probably through some precursor the exact 
chemical nature of which is not as yet known. It has, however, 
been shown that certain salts of ammonia, such as the carbon- 
ate, lactate, and carbamate are transformed into urea by the 
liver, as well as are leucin and glycin. The urea precursor in 
the muscles may be the lactate, since muscle activity gives rise 
to sarcolactic acid. 

Nitrogen excretion as the result of proteid metabolism: 
consists mainly of urea, to a certain extent of ammonium 
salts, and partly of uric acid and nitrogen " extractives." In 
health, metabolism of the proteids results not only in the 
excretion of the nitrogenous substances. It may be concluded 
that the proteid molecule gives rise in the body both to carbo- 
hydrates and to fat ; so that proteid metabolism, both in health 
and disease, is a much wider question than the consideration 
of the amount of urea or ammonium salts which constitute 
some of the final products of the metabolism. Carbohydrates 
which result from splitting up of the proteid molecule are 
utilized in the body and give rise to carbonic acid and water. 
The fat is also partly utilized and partly stored. It cannot be 
too frequently insisted upon that in health and disease it is 
the protoplasmic cell that performs these chemical manipula- 
tions. Within the limits of health proteid metabolism may 



CARBOHYDRATE METABOLISM 427 

b>e increased or diminished according to the special needs of 
the tissues. In disease a diminution of cell activity is frequently 
seen resulting from many different causes : from conditions of 
the circulation of the blood, from impoverishment of the blood, 
or from an action on the tissues of some toxic agent. An 
increased destruction of the proteids of the body, or, to speak 
more correctly, an increased proteid metabolism, is frequently 
observed in diseased conditions, and mainly as the result of 
the action on the tissues of some toxic agent. An increased 
proteid destruction, as it is called, gives rise to different 
conditions: (1) To glycosuria in special cases (p. 442), (2) to 
an increased formation of urea and ammonium salts, (3) to 
the formation of by-products, such as acetone, diacetic acid, 
and y^-oxy-butyric acid, and (4) to an increased formation of 
sulphates and phosphates. 

The increased formation of urea is not always demonstrable 
in the urine, inasmuch as there may be retention of urea in the 
tissues. Such urea retention occurs in disease of the kidneys ; 
whether primary, as in Bright's disease, or secondary, as in 
congestion occurring in venous stasis from whatever cause. 
More particularly is urea retention the case if edema is 
present. In some cases, however, the increased proteid 
destruction in disease does not lead to an increased formation 
of urea, owing to the ammonium precusors of urea not under- 
going transformation in the liver. In such cases, therefore, 
a diminished arount of urea is excreted, and an increased 
quantity of ammonium salts, while there is an increase of 
these salts in the blood, and the presence of lactic acid in ap- 
preciable quantities both in the blood and urine. 

Carbohydrates. — The carbohydrates are transformed in the 
alimentary tract into maltose which, however, is not absorbed 
as such by the tissues, but is first transformed into dextrose, 
which is the only sugar found in the body. The other carbo- 
hydrate found is glycogen. Inosit or muscle sugar is not a 
carbohydrate. Blood contains 0.05 per cent, of dextrose. 
The relation of the absorbed sugar to glycogen has given 
rise to much experiment and controversy. The carbohydrates 
form but a small proportion of the body — not more than I 



428 CHANGES IN METABOLISM 

per cent. This bears, therefore, a very small proportion to 
the amount of carbohydrate food which is taken. The absorbed 
dextrose is therefore utilized at once by the body for providing 
heat and energy. The glycogen in the body, which disappears 
in starvation and in muscular work, is also utilized for the 
same purposes ; but all the glycogen in the liver is not derived 
from the absorbed sugar, and it has been shown that some, at 
any rate, is derived from proteid food. This is shown by the 
reappearance of glycogen in the liver on a proteid diet after 
the substance has been got rid of by severe muscular work, 
as well as in the formation of glycogen in the embryo chick, 
in the absence of carbohydrates. Fat given to an animal which 
has been starved and worked does not give rise to the appear- 
ance of glycogen in the liver. The administration of glycerin 
appears to prevent the loss of glycogen. 

Fats. — Fat being emulsified, and to> some extent broken 
up in the small intestine, the fat particles are absorbed by 
the intestinal mucous membrane, and undergo a transformation, 
no doubt in the cells, into the fat of the body, which is of 
different composition to the fats taken as food. Fat is 
stored up in the body in the connective tissues and in the 
liver, and is utilized as a source of energy and heat. Fats 
are also partly broken up (saponified) in the intestine, into 
glycerin and fatty acids, which combine with alkalies, forming 
soaps. All the fat in the body is not derived from fats taken 
as food. Some, at any rate, is derived from the proteids, and 
some from carbohydrates. 

It is thus seen that the proteids form by far the most 
important food stuff necessary to man in that the transforma- 
tion they undergo is not only one into the proteids of the 
body, but one in which they are broken up into a carbohydrate 
moiety and a fatty moiety. Moreover, the carbohydrates 
increase the fat of the body in a way not yet completely 
understood. 

Of the salts taken in with the food, but little need here 
be said. Chlorid of sodium is a necessity of vegetable feeders, 
and when the diet consists of foods containing an excess of 
potassium salts and phosphates. The relation of the salts 



METABOLIC CHANGES DUE TO FOOD 429 

taken in with the food to the salts excreted is discussed under 
the heading of Urine Excretion (p. 399). 

Changes in Metabolism in Disease. — The nutrition of the 
body suffers in disease from many different causes. The chief 
causes are the following : 

1. The amount and character of food, and changes in the 
processes of digestion. 

2. Changes in the metabolism in the tissues of proteids, 
fats, and carbohydrates. 

3. Alterations in the circulation of the blood and in the 
composition of the blood. 

4. As the result of disease of the glands of the body. Duct- 
less Glands. Chapter XVIII. : Liver, Chapter XV. : Kidneys, 
Chapter XVI. : Pancreas (p. 444). 

5. Disease of the central nervous system (Chapter XIX.). 

6. As the result of the circulation of poisons in the body. 
The results of failure of nutrition are observed in the loss 

of body-weight, in changes in the body temperature, in changes 
in the excretory products, more particularly of the nitrogenous 
excretives and of carbonic acid, and in the presence of abnormal 
constituents or changes in the normal constituents of the urine. 

A. 1. Changes in Metabolism Due to Food. — Food may 
cause changes in nutrition if absolutely withheld, as in inanition 
or starvation; if greatly deficient, as in partial inanition, or if 
one or other of the essential food stuffs preponderate in the 
diet. 

Complete Inanition. — The effect of abstention from food has 
been studied experimentally, and is observed in some cases of 
disease, such as stenosis of the esophagus and of the pylorus, 
although both these instances may be considered in the majority 
of cases as examples of partial inanition. In complete inanition, 
which has been studied in the fasting men (Cetti. Breithaupt, 
Succi) as well as in animals, there has been observed a daily 
diminished loss of urea, which may, however, be at first 
excreted in greater quantity than normal, especially if a diet 
rich in proteid has been taken just previous to the fast. The 



430 CHANGES IN METABOLISM 

loss of urea and of nitrogen, as a rule, steadily diminishes and 
tends later to become more uniform : the average loss in the 
first ten days of starvation in well-nourished and healthy 
strong men being 10 to II grams of nitrogen. The loss 
of urea is diminished if the body is fat. When no proteid or 
other food is taken, the continued excretion of urea is due to 
the metabolism of the tissues, which draw on their own 
resources of proteid for their activity. This, as the starvation 
continues, leads to wasting of the tissues and to their diminished 
activity. The tissues, however, after a certain period, appear to 
get accustomed to a lower normal nitrogenous metabolism, as 
shown by the fact that the excretion of nitrogen tends to 
become uniform after the first two weeks of fasting. 

The loss of carbonic acid from the lungs is proportional to 
the weight of the body, to the amount of work done and, 
inversely, to the surrounding temperature. The amount 
excreted diminishes with starvation and represents the com- 
bustion not only of proteid, but of fat. The glycogen in starva- 
tion rapidly disappears from the liver and the muscles, so that 
the fat and proteids of the body are the only substances 
which give rise to the formation of carbonic acid by com- 
bustion. 

The temperature of the body is at first maintained, but 
afterwards falls to subnormal. Artificial warmth, or the pre- 
vention of the loss of heat from the surface of the body, tends 
to prolong the life of the starving individual. 

The loss of body-weight is due to loss of water in the urine, 
by the skin, and from the lungs, and to the loss of the tissues 
in fat and proteid which are utilized in maintaining the proc- 
esses of the body. The tissues of the body do not waste 
equally. The muscles and the fat are most affected, the former 
accounting for over 40 per cent, of the total loss of weight, 
and the latter for over 25 per cent. (Voit.) The skin, liver, 
and blood are the tissues next most affected, but their loss in 
weight is far behind that which occurs in the muscles and 
fat. The central nervous system and the heart show the 
least loss. 

As regards the actual weight lost particulars have' been 






INANITION 43 1 

obtained from the fasting men. Death occurs if the total 
weight lost is one-third of the original body-weight. Succi. 
in thirty days' fast, had his weight reduced from 62.5 to 52 
kilos., a loss of 10.5 kilos., or over 23 lbs. The loss up to the 
fifth day was 5.1 per cent., and up to the tenth day 9.3 per cent., 
of the weight. Cetti lost, up to the fifth day, y.y per cent, of 
his weight, and up to the tenth day 1 1. 1 per cent, of the original 
weight of 57 kilos. 

The effect on the excretions is seen in the diminution 
and final cessation of the passage of the motions, which at 
first consist of the undigested remnants of the food eaten 
before the fast, and afterwards mainly of the secretion of the 
digestive juices and of some epithelium and mucus. The 
digestive secretions are greatly diminished in starvation. The 
saliva is less in amount, but the diastatic activity, although 
greatly diminished, is not completely lost. Very little gastric 
juice is secreted and the amount of bile is also diminished. 
It is said that sugar does not completely disappear from 
the blood. The leukocytes of the blood are diminished in 
number. 

The effect on the urine is shown in the diminution of the 
quantity excreted. The amount of urea has already been 
discussed. The urates are diminished in quantity, as well as 
the creatinin. The chlorids are much diminished. On the 
tenth day of Cetti's fast only 0.6 gram was excreted in 
the urine in twenty- four hours, as compared with the normal 
of about 6 grams. The urine also shows another change 
in the increased quantity of acetone present. The quantity 
of acetone present in normal urine is about 0.0 r gram in 
twenty-four hours, but in inanition the amount present may 
be nearly fifty times this quantity, as was observed during 
Cetti's fast. Aceto-acetic acid and /j-oxy-butyric acid are 
also found in the urine, neither of them being present in 
the normal condition. Although acetone is a product of lactic 
acid fermentation, its presence in the urine in inanition must 
be considered as due to proteid disintegration. 

Partial Inanition. — Complete inanition is rarely the result 
of disease. Partial starvation, however, not uncommonly 



43^ 



CHANGES IN METABOLISM 



occurs mainly from disease directly affecting the alimentary 
tract and its glands. The effect of partial inanition is due 
to an incomplete diet : that is, one deficient in all its 
constituents. 

The nitrogenous exchange in partial starvation shows that, 
although the daily amount of nitrogen taken is below the 
normal amount of 15 grams, the patient may store up some 
of this nitrogen, as the following example shows (van ■ Noor- 
den). The patient was a female with stenosis of the gullet 
produced by caustic alkali, and was unable to take a normal 
quantity of food for many weeks. During a certain period, 
the analysis of the nitrogen in the food and that excreted gave 
the following results : 



Daily Intake. 


Daily Output of Ni- 
trogen in Urine 
and Feces. 


Daily Storage of 


N. 


Calories of 
Total Food. 


Nitrogen. 


7.602 


765 


5.915 grams. 


1.687 grams. 


8.991 


881 


7.041 " 


1.950 " 


11.77 


IOOO 


8.180 


3-590 '* 


13.67 


1 100 


8.830 " 


4.840 " 



The nitrogen thus stored up is used for energy, but little 
fat being deposited. 

The loss of weight which occurs in partial inanition as 
observed in disease varies considerably. As examples of 
severe cases may be quoted : a case of stenosis of the gullet 
(non-malignant), in which the body-weight fell from 100 lbs. 
to 73 lbs. in six and a half weeks, a loss of about 27.5 per cent. ; 
a case of severe ulcer of the stomach, in which the weight fell 
from 112 lbs. to jy lbs. in five to six weeks, a loss of about 
31 per cent. ; and a case of pyloric stenosis due to ulcer, in which 
the weight fell from 161 lbs. to 86 lbs. in the course of two and 
a half years, or a loss of over 46 per cent. 

The loss of weight in partial inanition depends on many 



METABOLIC CHANGES DUE TO EOOD 433 

factors, not only on the amount of food taken, but also on the 
digestive power of the organs and the power of assimilation of 
the tissues. The loss is also more marked in fat people than 
in the lean and muscular. 

What has been said as to the effect of complete inanition 
on secretion and excretion applies also to partial inanition, 
although to a less extent. 

The body temperature in partial inanition is almost 
constantly subnormal, there being but little daily excursion 
of the temperature curve: such individuals experience cold 
extremities. 

Preponderance of Proteids, Fats, or Carbohydrates in the 
Diet. — Although 15 grams of nitrogen is the minimum 
amount required for the maintenance of health, yet larger 
quantities are constantly taken. If the proteid in the diet is 
largely in excess of the requirements of the body, the excess of 
proteid appears in the urine as urea. The urea, therefore, 
increases in proportion to the amount of proteid food, and a 
nitrogenous equilibrium is established. An excess of proteid 
food thus leads to increased strain on the digestive and excre- 
tory organs and an increased metabolic activity on the part of 
the tissues, and the body wastes in many instances, owing to the 
utilization of the stored fat for the supply of energy and heat. 

An excess of fat in the dietary, with a diminution of the 
proteid food, leads to disintegration of tissue, owing to the 
deficiency in nitrogen. There is a large deposit of fat, owing to 
the excess of fatty food. Beyond a certain amount, which is 
about 2 ounces of fat daily, the extra fat is passed out in the 
feces unaltered, or partly broken up into fatty acids which 
combine with calcium. With an excess of fat, as also with an 
excess of carbohydrates, and a diminution of nitrogenous food, 
there is a condition of partial inanition. Excess of carbo- 
hydrates, besides leading to digestive disturbance, leads to the 
deposit of fat. 

B. Changes of Nutrition Due to Altered Processes of Diges- 
tion. — The nutrition of the body may suffer, owing to changes 
which occur in the digestive process in three directions, all of 
28 



434 CHANGES IN METABOLISM 

which result in a deficient amount of food passing from the 
alimentary tract into the tissues. 

1. There may be delay or obstruction to the passage of 
food along the alimentary tract. This occurs more particularly 
in obstruction to the passage of food by stenosis of the upper 
alimentary tract ; for example, of the gullet, of the two orifices 
of the stomach, and of the duodenum; or to retention of the 
food in the stomach or small intestine, owing to weakness 
(atony, myasthenia) of the muscular coat. 

2. Alterations in the chemical processes of digestion occur 
in the stomach, where the gastric mucous membrane may 
secrete in some cases an excess of hydrochloric acid, in other 
cases, a diminished quantity. In the latter case, in addition, 
there may be fermentation of the food, more particularly of 
the carbohydrates, which are broken up into products not 
utilized by the body for its nutrition. Following changes in the 
pancreas, a diminished amount of secretion enters the small 
intestine ; and in this, sometimes, bacterial fermentation occurs. 

3. A deficiency in the absorption of food not infrequently 
occurs, sometimes in functional disorders of the stomach and 
intestine, although not to< any great extent, but more par- 
ticularly when there is either portal obstruction, disease of 
the mesenteric glands, or of the thoracic duct itself. 

When there is actual obstruction to the passage of food, as 
occurs particularly in stenosis of the esophagus and of the 
pylorus, the effect on nutrition is well marked, and is that 
already described under the heading of Partial Inanition. 
With the delay of passage of the food due to deficient peri- 
stalsis, the failure in nutrition is not so marked as in actual 
obstruction, but is more marked when the stomach is affected 
than when the small intestine is the seat of the disorder. In 
such cases the loss of weight and the general effects of partial 
inanition are due not so much to the delay of food as to the 
deficiency of food taken. 

Changes in the chemical processes occurring in the stomach 
may have a profound effect on the nutrition. Where an excess 
of hydrochloric acid is secreted, as in cases of gastric irritation 
and in some cases of ulcer, there is a rapid and efficient diges- 



METABOLIC CHANGES DUE TO INDIGESTION 435 

tion of the proteid food, but a diminished digestion of the 
carbohydrates not only in the early part of gastric digestion, 
but during their digestion in the small intestine, owing to 
the hyperacid stomach contents rendering the contents of the 
small intestine too acid. The digestion of fat is, however, 
not affected. In cases of hyperchlorhydria there is, as a rule, 
no profound effect on nutrition except in those cases where a 
deficiency of food has to be taken on account of the digestive 
distress. When there is a marked deficiency in the secretion 
of hydrochloric acid there may be the effects of partial inani- 
tion, owing to the fact that the digestion of proteid foods is 
very poor, although the digestion of fats and carbohydrates is 
not affected. In the severe cases of hypochlorhydria, such as 
occur in gastric catarrh and in cancer of the stomach, bacterial 
fermentation of the food further increases the failure of nutri- 
tion, inasmuch as the carbohydrates are split up mainly into lac- 
tic acid, butyric or acetic acid. Deficiency in the amount of hy- 
drochloric acid (hypochlorhydria) and of pepsin occur in catarrh 
of the stomach, cancer, and in atrophy: the effect on nutrition 
is profound, owing mainly to the diminished quantity of food 
taken, but partly to the inefficient chemical processes of digestion. 
But little is known of functional alterations in the secretion 
of pancreatic juice, but when the pancreas is diseased, as in 
chronic pancreatitis, the secretion is deficient, and there is 
failure in nutrition, due partly to the inefficient digestion of 
the food in the small intestine. The effect of the pancreas on 
nutrition does not relate solely to deficiency of secretion, as 
it has an influence on the metabolism of carbohydrates and 
the production of glycosuria (p. 444). Bacterial fermentation 
of the food may occur in the small intestine, affecting mainly 
the carbohydrates. As a rule, however, no profound effect on 
nutrition is observed in such cases. Recent researches show 
that the mucous membrane of the duodenum and jejunum 
has an effect on pancreatic secretion. A substance, secretin, 
is extracted from the mucous membrane which, when injected 
into the body, sets up active pancreatic secretion (Starling). 
The bearing of these results on the explanation of disease can- 
not at present be estimated ; but they are of great importance. 



436 CHANGES IN METABOLISM 

Changes in the absorptive processes may affect nutrition 
either slightly or profoundly. Thus absorption of the food 
is diminished in cases where there is deficient digestion of 
the food, as in cases of hypoehlorhydria, and when there is 
weakness of peristaltic action. The failure of nutrition 
observed is, however, slight, and extended over a long period. 
When, however, there is organic obstruction to the absorption 
of food, the failure in nutrition is well marked. This occurs 
in portal obstruction, chiefly due to cirrhosis of the liver, and 
is one of the main causes of the failure in nutrition observed 
in that disease. It also* occurs, however, in disease of the 
mesenteric glands and of the thoracic duct, which is commonly 
tuberculous in origin. Obstruction to the portal circulation 
affects mainly the absorption of the proteids and the dextrose, 
while obstruction in the mesenteric glands or thoracic duct 
affects mainly the absorption of the fats'. In obstructed 
lacteal absorption the portal system cannot absorb the fats, 
but when the portal system is obstructed the lymphatics of 
the mesentery can absorb the proteids and dextrose, and 
this they may do to a greater extent than normally occurs. 

2. Changes in the Metabolism in the Tissues. 

A. Proteid Metabolism. — The general results of changes 
in proteid metabolism in disease are discussed under their 
appropriate headings, such as the pathological process of 
pyrexia, disease of the liver, and so on. There remains for 
special consideration the subject of uric acid. 

Relation of Uric Acid and Urates in Disease. — The amount 
of uric acid excreted from the body and its relation to the 
fluids of the body are of great importance in certain diseased 
conditions, more particularly gout; and although knowledge 
is still imperfect on the subject, the following physiological 
facts have a bearing on pathology. 

Origin of Uric Acid in the Body. — The uric acid excreted 
in mammals is, no doubt, in part clue to the metabolism of 
proteids. Its mode of origin, as well as the organs forming 
it, has been much discussed. In birds, in which the nitrog- 



URIC ACID 437 

enous excretion is mainly in the form of uric acid, the liver 
is the seat of its formation, and its precursor is lactate of 
ammonia, inasmuch as after extirpation of this organ uric acid 
is no longer excreted, but lactic acid and ammonia. Urea 
also given to birds is passed out of the body as uric acid. 
Uric acid given to mammals is transformed by the liver into 
urea before being excreted. The commonly accepted opinion 
is that in man uric acid is formed in the liver and possibly 
in the spleen, the precursors being possibly the same substances 
that are transformed by the liver into urea. It has, however, 
been asserted that the kidney is the organ which forms the 
uric acid. Analogy with birds would suggest that the liver 
is the organ concerned in its formation; but the process of 
formation in mammals may not be the same as in birds. 
Some, at any rate, of the uric acid is derived from the food. 
The uric acid in the urine is therefore of exogenous origin, 
that is, derived from the food ; and endogenous, that is, derived 
from the metabolism of the tissues. The exogenous uric acid 
is derived mainly from those foods containing nucleo-proteids, 
such as solid organs, liver, and sweetbread. 

With the uric acid must be considered the other substances 
which are classed as purin bodies. These bodies are hypo- 
xanthin (mono-oxy-purin) (,C.H 4 N 4 0) ; xanthin (di-oxy- 
purin) (C B H 4 N 4 O a ); uric acid (tri-oxy-purin) (C 5 H 4 N 4 3 ); 
guanin (C 5 H 5 N 5 0) ; and adenin (C 5 H 5 N 5 ). All these sub- 
stances are closely united with nuclein or nucleo-proteid in the 
diet. The purin bodies of food are no doubt liberated during 
the digestion of the nucleo-proteid, as in the following table 
(Horbaczewski) : 

Nulein or Nucleo-Proteid 



Proteid. Nucleinic Acid. 



Phosphoric Acid. f C 5 H 4 N 4 — NH— Adenin. 

C5H4N4O-NH— Guanin. 



•j C5H4N4O— Hypoxanthin. 

C ft H«N 4 9 — Xanthin. 
L C 5 H 4 X 4 O a — Uric acid. 



438 CHANGES IN METABOLISM 

It has been found that the pur in-containing foods lead to an 
increase in the excretion of purin bodies in the urine as com- 
pared in the same individual when foods not containing purins 
are eaten, such as eggs, milk, butter, cheese, and bread. The 
proportion of these bodies due to exogenous origin — that is, 
derived from food — may thus be ascertained. 

Variations in the Amount of Uric Acid Excreted. — The 
amount of uric acid daily excreted varies between 0.2 and 1.4 
gram, the average amount being 0.8 gram. The amount 
has been said to bear a definite relation to the amount of urea, 
so that a uric-acid-urea ratio is spoken of. There is, however, 
no definite ratio, as in health it varies considerably with different 
diets. The ratio with a bread diet is 1 : 81, with beef 1 : 48 
(Bunge, quoted by Hopkins). In normal conditions of diet 
and living, although there are great individual variations in 
the amount of uric acid excreted, the uric-acid-urea ratio is 
1 : 35, or 1 : 40. 

The amount of uric acid is increased in new-born infants, 
a considerably greater quantity of nitrogenous excretion being 
in the form of uric acid than is the case with adults. Other 
conditions in which the uric acid is increased are, excessive 
exercise, leukemia (p. 455), and leukocytosis, and in the two 
last conditions the increase appears to be associated with the 
presence of an excess of white cells in the blood, which no doubt 
degenerate and give rise to free nucleo-proteid. The increase 
of uric acid in this case, therefore, pathologically is due to 
the same cause as the taking as food of a solid organ, such 
as the thymus and sweetbread. Pilocarpin and salicylates 
also increase the amount of uric acid in the urine, and the 
amount is diminished by rest and in chronic gout. 

Solubility of Uric Acid and of Urates. — Uric acid does not 
exist as such in the tissues, nor in normal conditions in the 
urine. It combines with caustic alkalies to form neutral urates 
(M 9 U; M— metal, U— uric acid) which do not exist in the tis- 
sues or urine. It combines with alkaline salts to form biurates 
(MHU), such as sodium, potassium, and ammonium urates. 
This is the form in which uric acid is deposited in the tissues, as 
in gout. Uric acid also exists in the more soluble form of quad- 



URIC ACID 439 

riurates (H 3 UMHU), and it is in this form in which the uric 
acid of birds is excreted, and presumably the form in which the 
urates exist in the human urine and the tissues (W. Roberts). 

The study of the solubilities and deposition of the biurates 
and of the quadriurates becomes of great importance in the 
discussion of diseased conditions, more particularly of gout. 
The biurate investigated has been chiefly the sodium salt, and 
the following important facts have been ascertained (W. 
Roberts). Sodium biurate is soluble in iooo parts of distilled 
water at ioo° F. Its solubility is diminished by adding sodium 
salts to the solution, either by themselves or in such liquids 
as blood serum, lymph, and synovia: a deposit is formed of 
sodium biurate. This salt is very slowly soluble in serum or 
synovia, as are the gouty deposits in cartilage which water 
dissolves quickly. Uric acid dissolves in serum ( i in 500) and 
in synovia as a quadriurate. On standing, however, the liquid 
soon deposits crystals of sodium biurate; the changes being 
accelerated by keeping the liquid at the body temperature. 
They are in proportion to the amount of uric acid dissolved. 
The deposit of sodium biurate from the solution of uric acid 
in serum is sometimes sudden and complete. 

These results have been utilized to explain the deposit of 
sodium urate in the tissues in gout. Two conditions are nec- 
essary : an excess of uric acid in the blood (uricemia), and the 
process of deposition or uratosis. The uric acid circulating 
as quadriurate is increased in the blood in gout. Circulating 
in tissues containing a large proportion of sodium salts, this 
excessive amount of quadriurate is suddenly transformed into 
sodium biurate. which is deposited in the cartilage of the joints 
affected. It is found that the tissues in which sodium biurate 
is deposited in gout are richer in sodium salts than those in 
which the salt is not deposited. Thus a larger proportion of 
sodium salts is found in blood serum, lymph, and fibrous tissue 
(o.y per cent.), in synovia (0.8 per cent.), and in cartilage 
(0.9 per cent.), in which sodium biurate is deposited in gout, 
than in the brain (0.2 per cent.), liver (0.08 per cent.), spleen 
(0.04 per cent.), and muscle (0.08 per cent.), in which deposits 
do not occur. 



44 o CHANGES IN METABOLISM 

The deposit in gouty joints consists mainly of sodium 
biurate, which is incrusted on to the cartilage, and is found 
in the cartilage itself, but only superficially, gradually dis- 
appearing in the deeper parts. If the statements just made 
are correct, the deposition in the cartilage would occur in 
gout after imbibition from the synovia or blood vessels of 
the bone, and would be mainly a question of solubility due 
to the presence of an excess of sodium salts. It has been 
found experimentally that synovia, rich in uric acid, deposits 
biurate on the cartilage of dead joints in the same manner 
as is observed in gouty joints. It is this deposition which is 
supposed to give rise to the gouty paroxysm. A joint which 
has been affected with acute gout may be found afterwards 
to contain no deposit of biurate. It is supposed, therefore, 
that the deposit of biurate may be redissolved by the blood 
when this contains a diminished quantity of quadriurate. 
Whether the gouty paroxysm can occur without deposition 
of biurate is doubtful. Deposition of this salt is the main 
gross feature of the gouty attack. The analysis of tophi or 
deposits of biurates in fibrous tissues, shows that they consist 
mainly of uric acid and sodium, with a smaller quantity of 
potassium and still smaller quantities of calcium and mag- 
nesium phosphates, and sulphur. The amount of uric acid 
present is about 60 per cent, of the dried substance, of sodium 
oxid 9.3 per cent., and of potassium oxid about 2.95 per 
cent., the remainder of the substance consisting of small quan- 
tities of other minerals and of tissue, which is present in about 
28 per cent. 

There is no question of the deposition of biurate in the 
joints and tissues of gout. The amount present in the blood 
has been found to vary considerably. An excess was found 
in exudations in blister fluid and in the blood by the applica- 
tion of the murexid test, or by placing fibers of linen in 
the liquids mentioned, with the addition of a trace of acid. 
Crystals of uric acid were formed on the fibers. It was 
thus considered (Garrod) that there was an excess of uric 
acid in the blood, and that this was accompanied by a dimin- 
ished excretion. The amount of uric acid which has been 






GOUT 441 

found in the blood in gout has varied between 0.025 gram 
and 0.175 gram per 1000. Similar variations in the amount 
of uric acid have, however, also been found in chronic 
plumbism and renal disease, pneumonia, emphysema, and 
anemia. 

Other CJiauges in Gout. — In gout there are other changes 
in the body besides those which have been described in con- 
nection with uric acid. It has been found that the total nitrog- 
enous discharge is diminished in gout, the difference between 
intake and discharge being between 2 and 4 grams nitrogen 
daily. It is possible that this diminished output of nitrogen 
is associated with disease of the kidney (p. 395). The changes 
in metabolism are by no means always limited to variations in 
the nitrogenous substances of metabolism. 

In some instances gout is associated with glycosuria (p. 
446), with renal disease (granular contracted kidney) and with 
nervous symptoms, such as asthma. Whether those changes 
are to be ascribed or not to the presence of an excess of urates 
in the blood and tissues, is doubtful. The glycosuria would be 
ascribed to the general disorder of metabolism which occurs in 
the nitrogenous tissues. The explanation of the renal disease 
is not easy. It might presumably be due to some irritative 
substance which is excreted in the urine. It does not appear 
that the uric acid is the substance, as it is not excreted in excess 
in gout. By some the causation of the gouty kidney, as well as 
gouty asthma, has been ascribed to the circulation of some 
poison other than uric acid. There is no evidence, however, of 
the existence of such a poison, and at any rate the gouty kidney 
may be due to the same conditions which produce the gout, 
namely, dietetic irregularities. 

In the majority of cases gout is due to the abuse of alcohol 
and food, more particularly animal food, both of which lead to 
general disorder of metabolism. It is, however, remarked that 
gout is hereditary in many instances; families showing this 
particular tendency of disordered metabolism which leads to 
the formation of an excess of uric acid. The inheritance may 
be passed on through the males of a family, a generation being 
frequently skipped. 



442 CHANGES IN METABOLISM 

Carbohydrate Metabolism. — Disturbances in the carbohy- 
drate metabolism in disease are shown mainly in the occurrence 
of glycosuria, which exists in all degrees. Glycosuria has been 
experimentally studied, and the following facts have an impor- 
tant bearing on its natural occurrence in man. No distinction 
can at present be made between glycosuria and diabetes, al- 
though it is probable that the conditions may have different 
modes of origin. 

1. Puncture Glycosuria. — Puncture of the floor of the fourth 
ventricle near the vaso-motor center gives rise to glycosuria 
(Claude Bernard). With the glycosuria the glycogen of the 
liver disappears, being converted into sugar, which is thus 
in excess in the blood and is passed out in the urine. If 
glycogen is absent from the liver, as in a starved and worked 
animal, no glycosuria results. Other lesions of the nervous 
system are followed by glycosuria, such as injury to the vermi- 
form process of the cerebellum, destruction of the cervical 
sympathetic ganglia and of some of the other ganglia, and 
stimulation of the central end of a divided sensory nerve. No 
glycosuria occurs on division of the splanchnic nerves. 

One explanation of the occurrence of glycosuria after punc- 
ture of the floor of the fourth ventricle is that there is dilatation 
of the hepatic artery, which has the result of bringing some 
ferment to the liver cells, which, acting on the glycogen, con- 
verts it into sugar. In this case the condition would be due 
to stimulation of the liver cells. Whether this is so or not is 
not at present known. 

2. Toxic Glycosuria. — Certain toxic substances cause the 
appearance in the urine of bodies which reduce Fehling's solu- 
tion. These reducing bodies are either glucose or glycuronic 
acid. The following substances have this toxic action : phos- 
phoric acid, lactic acid, hydrochloric acid, strychnin, curare, 
phosphorus, arsenic, carbonic oxid, butyl-chloral hydrate, mor- 
phin, hydrocyanic acid, chloroform, turpentine. In most of 
these cases the copper-reducing substance is not glucose, but 
glycuronic acid. Glycuronic acid, COOH . (CH . OH) 4 . CHO 
is related to glucose, which may be represented by the rational 
formula, CH 2 HO . (CH . OH) 4 . CHO. It appears in the urine 



GLYCOSURIA 443 

only in pathological conditions and is apparently an incom- 
pletely oxidized product in the metabolism of carbohydrates. 
In the urine it is in combination with ethereal sulphates or 
other similar compounds (p. 404), or with some alcoholic sub- 
stances, such as chloral hydrate, butyl-chloral, and chloroform. 
Glycuronic acid appears in the urine mainly as the result of 
the ingestion of these substances, and not as the result either 
of the ingestion of carbohydrate food, or as the result of disor- 
dered carbohydrate metabolism. It reduces Fehling's solution 
when present in the urine, and is distinguished from glucose 
in not being fermentable with yeast. 

The presence of glycuronic acid in the urine has, as far as is 
known, but slight connection with the occurrence of glycosuria. 
This is otherwise with a glucosid, phloridzin, obtained from 
the root bark of the apple and cherry, to which the formula 
C 91 H Q4 O 10 H 20 has been given. Phloridzin, when injected sub- 
cutaneously, or taken by the mouth, produces glycosuria, and 
its action does not depend on the amount of glucose it contains, 
"but on an active principle, called phloretin, which is obtained 
from it. One gram of phloridzin has given rise to the excre- 
tion of 97 grams of sugar (Minkowski), so that the effect is out 
of all proportion to the amount of glucose the substance con- 
tains. It also produces an increased secretion of sugar in milk. 
The glycosuria is associated with a diminished quantity of 
glycogen in the liver, but is not solely, or even mainly, depend- 
ent on the metabolism of the glycogen, inasmuch as it persists 
after the glycogen of the liver has disappeared or been greatly 
diminished. Thus, in a starved and worked animal, phloridzin 
produces glycosuria, unlike puncture glycosuria. In this case 
the sugar must be derived from the metabolism of the proteids 
of the body, and that these are broken up more than normally 
is shown by the increased nitrogen excretion in the urine, which 
sinks or falls with the excretion of sugar. It also gives rise, 
when given in large quantities, to an increase of acetone, and 
to the presence of diacetic acid and /^-oxy-butyric acid (p. 
448) in the urine, and finally causes death in coma. 

It has been stated that in phloridzin glycosuria there is no 
excess of sugar in the blood, unlike what occurs in puncture 



444 CHANGES IN METABOLISM 

and pancreatic glycosuria, and the formation of sugar has been 
ascribed to the activity of the kidneys. It is not certain, how- 
ever, that this is the case, and some observers have found an 
excess of sugar in the blood in phloridzin glycosuria (Pavy). 
Tying the renal blood vessels before the injection of phloridzin 
leads to the accumulation of sugar in the blood. 

The mode of production of phloridzin glycosuria has not 
been explained. It is evident, however, that there is a profound 
effect on the nitrogenous metabolism of the body, and it is pos- 
sible that phloridzin acts directly on these substances, causing a 
splitting up, with an increased formation of a carbohydrate 
moiety, which is excreted as sugar. 

3. Pancreatic Glycosuria. — Total extirpation of the pancreas 
in dogs, cats, and pigs leads to glycosuria, sugar being present 
in the urine to the amount of 5 or 10 per cent., the blood con- 
taining as much as 0.46 per cent, of glucose (von Behring and 
Minkowski). This glycosuria is associated with the symptoms 
of natural diabetes in man, namely, excessive appetite and 
thirst, polyuria, wasting, and weakness. Great quantities of 
acetone, diacetic acid, /i-oxy-butyric acid and ammonia salts 
are present in the urine, and death occurs in coma in from ten 
to fifteen days. The nitrogen excretion, as in phloridzin 
glycosuria, goes pari passu with the amount of glucose in the 
urine. Total extirpation in these animals leads, therefore, to 1 a 
very complete reproduction of the symptoms of severe diabetes 
in man. If the organ is only partially extirpated, about one- 
third or even less being left, and this portion grafted on to* the 
abdominal wall with its vessels so as to preserve its vitality, no 
glycosuria occurs, nor any of the symptoms or signs above 
stated. If the grafted portion be extirpated later, the symptoms 
described are observed. When a tenth part of the pancreas is 
left in the body, glycosuria does not occur unless carbohydrates 
are given with the food. In this way, therefore, the milder form 
of diabetes in man is reproduced (p. 446). Feeding with pan- 
creas or injection of pancreatic extract does not relieve the 
symptoms of pancreatic glycosuria. The effect of extirpation 
is not dependent on the removal of the pancreatic secretion 
from the intestine since glycosuria and the other signs do not 



GLYCOSURIA 445 

occur if the pancreatic duct be ligatured, or its lumen be obliter- 
ated by the injection of paraffin. 

Twenty per cent, of cases of diabetes in man show disease of 
the pancreas (Frerichs), the disease being shown in atrophy of 
the organ, in fibrosis, or in cyst formation. It may be, however, 
that a gross naked-eye change does not necessarily occur in 
the pancreas when glycosuria results from disease of it. The 
pancreas consists of two portions : the acini of the glands 
connected with the ducts, that is, the parts secreting the pan- 
creatic juice; and certain collections of epithelium-like cells 
which are unconnected with the gland ducts. It may be the 
latter cells which play a part in the carbohydrate metabolism. 
The diminution of secretion of pancreatic juice evidently has 
no effect in the production of glycosuria, and the suggestion has 
been made that the islets of cells in the pancreas yield an inter- 
nal secretion which influences the carbohydrate metabolism. 
When this secretion is absent there ensues the presence of an 
excess of glucose in the blood, and so glycosuria. This, how- 
ever, is at present only an hypothesis. 

4. Alimentary Glycosuria. — This term is given to a slight 
glycosuria which occurs in certain healthy individuals after a 
meal rich in sugar, and it has been suggested that when a large 
quantity of sugar is taken it is absorbed, not by the portal 
vessels, but by the lacteals, so that it is not transformed into 
glycogen by the liver. Starch when taken as food does not 
lead to alimentary glycosuria. Dextrose given in quantities 
of 200 grams leads to glycosuria in half to one hour, the effect 
passing off in three to six hours and varying considerably 
in different individuals. Levulose behaves in the same way as 
dextrose, while cane sugar is sometimes discharged unchanged, 
and sometimes as dextrose. Lactose appears readily in the 
urine after large quantities are taken. Puerperal lactosuria is 
an example of alimentary glycosuria. Suckling women also, 
after partaking of 50 to 100 grams of lactose, not infrequently 
have lactosuria. The forms of sugar, called pentoses, also 
appear in the urine after administration (pentosuria). 

It js evident that alimentary glycosuria is quite another 
condition from the glycosuria produced either by puncture, by 



446 CHANGES IN METABOLISM 

phloridzin, or by pancreatic extirpation, and that it is only a 
question of absorption and non-transformation of the sugars. 

Glycosuria and Diabetes in Man. — As far as is known, these 
conditions occur naturally chiefly in man. The term glycosuria 
is frequently applied to the conditions where small quantities of 
glucose are excreted; diabetes to the severer forms where 
large quantities of glucose are present in the urine. No such 
distinction can be drawn from a pathological point of view, and 
all the conditions are to be considered as diabetes in a mild or 
severe form. The mild cases are those in which glycosuria 
only occurs when carbohydrate food is given, or when glucose 
is present in the urine with a moderate amount of carbohydrate 
— 50 grams, 100 grams, or 150 grams — in the daily diet. The 
severe cases are those in which glycosuria persists even if 
carbohydrates are withheld from the diet, and in these cases 
the carbohydrate present in the blood and tissues is not con- 
sumed. This glucose must be derived from the disintegration 
of the proteids of the body. It has been calculated that 100 
grams of proteid by the addition of H 2 and C0 2 may give 
rise to 113.6 grams of glucose; or, in other words, one part 
nitrogen is equivalent to 7.1 grams glucose (Moritz and 
Prausnitz). The excretion of nitrogen in the urine is greatly 
increased in diabetes, and may even be as high as 30 or 40 
grams of nitrogen daily: the normal being about 15.5 grams 
as a minimum. This increased discharge of nitrogen is due 
partly to the taking in of more proteid food. Thus 200 grams 
of proteid in the diet, which is not an excessive quantity 
for a diabetic to consume, would be equal to 32 grams nitrogen 
in the urine. But the increased nitrogen discharge is also 
due partly to increased destruction of the proteids of the body 
with the formation of glucose, and due in part to the toxemia. 
A patient weighing 49 kg. on a daily diet equal to 2320 calories 
excreted 34.5 grams nitrogen. The sugar excreted in the 
same time was 271 grams=ino calories. Only 1210 calories 
(2320 — 1 1 10) was the amount of the diet utilized in the body, 
and this was equivalent to a daily loss of 2 grams of nitrogen 
to the body. 



DIABETES 447 

Carbohydrates in the Urine. — In diabetes, glucose is the 
sugar which is almost invariably found. Occasionally small 
quantities of levulose or maltose are discovered, and, in rare 
cases, glycogen, the presence of which has been ascribed to 
retrans formation of the sugar in the kidneys. The amount of 
sugar which is daily excreted in cases of diabetes varies con- 
siderably, the average amount in severe cases, when carbo- 
hydrates are excluded from the diet, being about ioo grams per 
day, but as much as 200 grams, or more, daily, may be found 
in the urine. The amount excreted from time to time in 
the day varies considerably. As a rule, less is found in the 
morning urine than in the evening, after the day's food 
has been taken. Inosit is sometimes found in the urine in 
diabetes. 

Diabetic Coma. — The coma of diabetes is associated with 
symptoms which may also be present as a final stage of abdom- 
inal cancer and of pernicious anemia. The main features are 
those of stupor of gradual onset, deepening into coma which 
ends in death, there being at the same time an affection of the 
respiration, which becomes more rapid and deeper, and an 
effect on the heart-beat, which becomes more frequent and 
weaker. The temperature is usually subnormal, and con- 
vulsions sometimes occur. 

These symptoms are those of an intoxication, but the 
pathology of the condition has not yet been explained. The 
following facts may, however, have a bearing on the matter. 
The condition of the blood in diabetes is that of concentra- 
tion due to loss of water from the body by the polyuria. 
This is also observed in diabetes insipidus. But more im- 
portant than this is the diminished alkalinity of the blood 
which is due to an increase of acids, mainly of /?-oxy-butyric 
acid (Minkowski). Aceto-acetic acid is also present, as well 
as acetone. The blood of diabetics shows between 0.154 
and 0.576 per cent, of sugar, as compared with the normal 
variation of 0.05 to 0.12, and the amount of sugar bears a 
direct relation to the degree of glycosuria. By some, the 
phenomena of diabetic coma are ascribed to the presence of 



448 CHANGES IN METABOLISM 

fi -oxy-butyric acid, but this body does not produce the 
symptoms of diabetic coma, although it is said that the 
injection into animals of /?-amido-butyric acid gives rise to 
the symptoms of diabetic intoxication (M. Gruber). It has 
also been suggested that some of the precursors of the acid 
bodies found in the blood may act as poisons. The symp- 
toms may be produced by the injection into animals of dilute 
mineral acids, but this experiment has but little bearing on 
the subject. The perchlorid of iron reaction of the urine, 
that is, the purple color given with tinctura ferri perchloridi, 
is in many cases present at the onset of coma, but it may be 
absent; and, on the other hand, it may be present without 
coma ensuing. The increase of acetone in the urine in 
diabetes, and the presence of a large excess of aceto-acetic 
acid and /^-oxy-butyric acid, is a sign of the decomposition 
of tissue proteids, and the amount of these substances is pro- 
portional to the loss of nitrogen from the body. Acetone may 
be found in diabetic urine to the extent of 2, 5, or 10 grams 
a day. Of /?-oxy-butyric acid, 30 to 50 grams or more may 
be found daily, and the amount of this is diminished when a 
large amount of proteid food is given, so as to spare the tissue 
proteid. 

C. Fat Metabolism. — The metabolism of fat in disease is 
seen in two different conditions : in a loss of fat which occurs 
in wasting, the result of a failure in general nutrition ; or in an 
increase of fat which occurs in obesity. There is a physiolog- 
ical increase of fat at puberty and at the menopause, as well as 
at middle age in men. An increase of fat may otherwise be due 
to either an increase in the amount of food taken, or to a change 
in metabolism, in which, without an increase in the amount of 
food, more fat is deposited in the body. 

The obesity due to overeating is readily explained by the 
consideration that, after the needs of the body have been sup- 
plied as regards the necessary nourishment of tissues in relation 
to work and heat, the excess of absorbed food is deposited 
mainly as fat. This explanation does not apply, however, to 
many cases of obesity which are not due to overeating. Obesity 



METABOLISM IN CYANOSIS AND DYSPNEA 449 

follows castration both in the male and female; it is in 
many families hereditary and may in this case appear 
in youth, in adult life, or middle age. It is sometimes 
associated with chronic alcoholism, and occurs after infect- 
ive disease, and is not infrequently associated with glycosuria. 
One obscure nervous disease, adiposis dolorosa, is associated 
with large deposits of fat in various parts of the 
body, and sometimes with atrophied thyroid. 

Metabolism in the obese is diminished. There is a 
decrease in the body heat, a decreased consumption of 
oxygen, and a decreased output of carbonic acid. There is 
not infrequently oxaluria, which may possibly be taken as 
a sign of diminished oxidization. A complete explanation 
of the occurrence of obesity, when not due to an excess of food, 
is not forthcoming. It is, however, possible that the condition 
is due to a changed metabolism, by which, from the proteids 
taken as food or present in the body, a greater quantity 
of fat is formed than normal. By some the condition is 
said to be explained by speaking of a " retardation of 
metabolism. " 

3. A. Metabolism in Disorders of Respiration and Circula- 
tion. — Metabolic changes in the disorders of respiration and 
circulation may be considered together, as in many instances 
the conditions are combined. The changes of respiration 
which here come for consideration are those in which there are 
respiratory defects leading to dyspnea (p. 279), and second- 
arily to circulatory defects, such as venous stasis. The changes 
in the circulation to be discussed are those concerned in venous 
stasis, and are due to such primary conditions as valvular 
disease and dilatation of the heart, or disease of the lungs. 
Respiratory defects, such as result from destruction or incapac- 
itation of a portion of the lung, as in pneumonia or tubercu- 
losis, or from a loss of elasticity of the lung, as in emphysema, 
affect mainly the respiratory exchange in the blood. Venous 
stasis not only affects the respiratory exchange, but the activity 
of other organs in the body, and more particularly of the liver 
and kidneys, as they are so prominently concerned in metab- 
29 



450 CHANGES IN METABOLISM 

olism. The liver, for example, becomes congested and some 
atrophy and fatty degeneration of the cells occur, while the 
kidneys show mechanical congestion. 

Respiratory Exchange in Cyanosis and Dyspnea. — In simple 
forms of cyanosis, such as are observed in uncomplicated 
mitral disease and in congenital cardiac disease, the respiratory 
exchange in the lungs is not deficient and is not markedly 
different from the normal. Sufficient oxygen is taken into 
the blood and a corresponding quantity of C0 2 discharged. 
The duskiness of the extremities — fingers, nose, and ears — is 
explained by the slow circulation of the blood in the capil- 
laries of these parts. The oxygen is taken up completely by 
the tissues from the blood, leading to the dark color of the 
part. There is no general deficiency of oxygen, therefore, but 
only a local deficiency due to an increased absorption of the 
oxygen of the blood by the tissues. When, however, there is 
a respiratory defect, either primary or secondary to the cardiac 
lesion, associated with the resulting dyspnea, there is a defi- 
ciency of oxygen taken into the blood and an excess of C0 2 
present, and this is the condition present in dyspneic and 
asphyxial states. The deficiency of oxygen and the increase 
of C0 2 vary considerably in amount and in proportion, not 
only to the amount of lung damage, but to the degree of com- 
pensation possible (p. 290). When into a small portion of lung 
the air enters with difficulty, the blood from the pulmonary 
artery supplied to that area does not efficiently discharge its 
CO 2 or take in oxygen. This blood, therefore, mixing with 
the blood from other efficiently acting parts of the lung, dimin- 
ishes the total oxygen in the blood. The main compensation 
in chronic lung conditions for this diminished quantity of 
oxygen is that the tissues adapt themselves to a lessened supply 
of oxygen (p. 292). 

Effect of Cyanosis and Dyspnea on Digestion and Proteid 
Metabolism. — In all but severe cases the secretion of the 
digestive juices and absorption go on practically normally. 



METABOLISM IN CYANOSIS AND DYSPNEA 451 

When, however, in conditions of deep cyanosis there is con- 
gestion of the stomach, the amount of hydrochloric acid in the 
gastric juice is greatly deficient. As a rule, the absorption of 
carbohydrates and proteids is good ; that of fats is diminished 
in some cases. 

There are no very accurate data for discussing the proteid 
metabolism in dyspnea and cyanosis in man. In experimental 
dyspnea in dogs an increased proteid metabolism is observed, 
ascribable. it is supposed, to death of a certain number of 
cells of the body, but it cannot be said with certainty that a 
similar increased metabolism occurs in man. On the whole, 
it may be said that the nitrogenous excretion is not increased. 
This cannot be taken as an accurate indication of the amount 
of urea which is formed in dyspnea and cyanosis, for there 
is no doubt that some of the urea is retained in the body, 
more particularly in the edema fluid. Uric acid is not 
increased except in very severe cyanosis, or just before 
death. An increased quantity of urea is found in the urine 
in some cases when diuresis is produced by digitalis. Cases 
may be divided into three groups (Kobler, quoted by von 
Noorden). 

In the first group, the diuresis produced by digitalis is accom- 
panied by an increased excretion of urea and to some extent 
of uric acid, as in the following table : 

Daily amount of Urine . 420 400 730 1100 740 c. c. 

Urea 9.01 9.28 20.44 23.43 17.83 grams 

Uric Acid .... 0.53 0.52 0.74 0.98 0.75 

Thus, with the diuresis, there occurred an enormous excre- 
tion of urea which is to be considered as the excretion of the 
urea retained in the body. 

In the second group of cases, while digitalis produced 
diuresis, the amount of urea was but slightly affected : 



Daily amount of Urine . 500 1050 2200 1850 550 620 c. c. 

Urea 10.9 14.8 15.6 13.5 11. 5 12.6 grams 

Uric Acid .... 0.29 0.32 0.4 0.5 0.15 0.22 " 



452 CHANGES IN METABOLISM 

In the third group of cases there was but little diuresis, but 
the urea was greatly increased. 

Daily amount of Urine . . 320 200 700 450 510 c. c. 

Urea 8 64 5.88 21,42.. 12.82 13.43 grams 

The increased excretion of urea did not last longer than 
two to four days, and it may be greater than the figures 
given above. 

The excretion of ammonium salts increases with that of 
the urea, while that of creatinin, in severe cases of want of 
compensation, is diminished. 

With the consideration of the nitrogenous excretives must 
be taken that of lactic acid, which is present not only in the 
blood, but in the urine. It is observed not only in dyspneic 
and cyanotic conditions in man, but also experimentally in 
dogs, as in artificially produced dyspnea and in poisoning by 
carbonic oxid, phosphorus, morphin, amyl nitrite, cocain, 
veratrin, curare, and strychnin. The amount in the urine 
appears to be proportional to the degree of dyspnea, and its 
presence may possibly be due to an affection of the liver, the 
normal amount of lactic acid and ammonia not being trans- 
formed into urea. Glycosuria is not observed in dyspnea or 
in cyanosis in man, but it is present in dyspneic conditions 
experimentally produced in dogs. The oxalic acid in the urine 
is increased. 

4. B. Metabolism in Anemias and in Leukemia. 

1. Anemias. — The conditions included under this head are 
(Chapter XL) chlorosis, pernicious anemia, acute anemia fol- 
lowing hemorrhage, and secondary anemias. The conditions 
are widely different pathologically, and have one common 
factor, the diminution in the amount of hemoglobin in the 
blood. Pernicious anemia and many secondary anemias differ 
from chlorosis and acute anemia in that there is some toxic con- 
dition present. The changes in metabolism to some extent 
depend on this factor. 

(a) The Oxidization Processes. — A diminution in the amount 
of hemoglobin in anemia, of whatever kind, would lead to 



METABOLISM IN ANEMIA 453 

the supposition that the oxidization processes of the body- 
are diminished, owing to a deficiency in the oxygen-carrying 
substance in the blood ; but the rate of exchange of oxygen and 
CO a has not been found to be widely different from the normal. 
In anemia experimentally produced by bleeding in dogs, it has 
has been found that the respiratory exchange is not different 
from the normal, and experiments performed in pernicious ane- 
mia, chlorosis, and in secondary anemia, show a like result, as 
well as in leukemia. Inasmuch as the oxygen carrier is dimin- 
ished in amount, it is evident that there must be some compen- 
sation for the loss of hemoglobin, and the compensation prob- 
ably is due partly to increased activity of the heart, and partly to 
increased rapidity of the breathing. In this case, although 
the hemoglobin is diminished, what is present does its work 
more quickly than in normal conditions, owing to the increased 
rapidity of circulation of the blood and the increased rapidity 
of the respiratory exchange in the lungs. In the tissues in 
anemia, the hemoglobin parts w T ith nearly all its oxygen, so 
that the venous blood is more deficient in oxygen than it is in 
normal conditions. There may be, however, a degree of ane- 
mia in which the hemoglobin is not sufficient to keep up the 
normal respiratory exchange, and in such cases, which mainly 
occur in pernicious anemia or severe secondary anemia, there 
is some evidence of diminished oxidization in the tissues. 
Thus, lactic acid may be found in the urine. It is present in 
experimental anemia, but in human anemia its appearance is 
very irregular. The fatty degeneration of the glands and 
heart muscle which occurs in anemia is no doubt due to the 
anemic condition, and has been explained as the result of 
deficient oxidization (p. 202.) Such degeneration, however, 
only occurs in severe forms of anemia, and is possibly associated 
with an increased and imperfect metabolism of the tissues. 

(b) Effect on Digestion and Proteid Metabolism. — The se- 
cretion of hydrochloric acid in chlorosis is, as a rule, not dimin- 
ished. The percentage varies between 0.26 and 0.58 grams. In 
twenty-five cases examined by von Noorden, eight showed an 
increase of hydrochloric acid, eleven showed the normal quan- 
tity, and six showed a diminished quantity. In severe perni- 



454 



CHANGES IN METABOLISM 



cious anemia, on the other hand, the secretion of hydrochloric 
acid may be greatly diminished, and in the acute exacerbations 
it may be present in the gastric juice in only very small quanti- 
ties. Both in chlorosis and in pernicious anemia the absorption 
of fat may be affected. 

Proteid metabolism is not affected in chlorosis to any great 
extent, and the nitrogenous equilibrium is readily maintained, 
as shown in the following table of three cases investigated 
(von Noorden) : 





Duration of 
Experiment. 


Daily 
Nitrogen 
in Food. \ 


Calories 

per Kilo. 

Body-Weight. 


Nitrogen in 

Urine and 

Feces. 


Daily'Nitroger. 

Stored 

in the Body. 


Case I. 


7 days. 


12.88 g. 


38 


12.82 g. 


-r- 3.06 g. 


Case II. 


7 days. 


13.06 g. 


37 


12.68 g. 


+ O.38 g. 


Case III 


9 days. 


12.92 g. 


37 


12.21 g. 


+ O.71 g. 



In acute anemia, however, produced experimentally by 
bleeding dogs, an increased excretion of nitrogen was found 
soon after the loss of blood, and a similar increase has been 
observed in severe pernicious anemia. This increased proteid 
destruction in pernicious anemia is, however, not to be ascribed 
to the condition of anemia, but to the condition of intoxication 
present. In pernicious anemia, the amount of uric acid 
excreted is diminished in relation to the other nitrogenous 
substances, but there is no change in the chlorin equilibrium. 
There is a diminution in the chlorids in the urine after 
hemorrhage. 

2. Leukemia. — What has been stated about the respiratory 
exchange in anemias applies to leukemia, which, strictly 
speaking, is not an anemic condition until the disease is 
well advanced (p. 315). Proteid metabolism in leukemia 
exhibits certain peculiarities which contrast strongly with 
those in anemia. There is increased proteid metabolism 
which is very irregular in extent in individual cases, the 
destruction of proteid being apparently in some relation to 
the number of leukocytes in the blood. Albumoses are found 



METABOLISM IN LEUKEMIA 



455 



in the blood and their amount is increased after death. An 
analysis of leukemic blood by Freund and Obermeyer (quoted 
by von Noorden) shows that the percentage of albumoses is 
about 1.23 as follows: 





Composition (Percentage) of 




Leukemic Blood. 


Normal Blood. 


Water 


89.58 




77-9 


Total Solids 


IO.42 




22.1 


Proteid and Hematin . . . 


7.2 




21.27 


Albumoses 


I.23 




• • 


Fat 


O.71 
O.31 


1 
1 

f 

J 




Lecithin 


O.I6 


Cholesterin 


O.21 




Salts . . . 


O.98 




O.78 





As regards the mineral constitutents, phosphates, sodium 
and sulphates are greatly increased ; while chlorids, potassium, 
calcium, ammonium, and iron are greatly diminished. Besides 
this, the chief chemical characteristic of leukemic blood is the 
presence of albumoses, and a large quantity of lecithin, fat, and 
cholesterin. which, with the phosphates, are derived from the 
white blood corpuscles, these being included in the analysis. 

The amount of urea, in so far as it has been examined in 
leukemia, does not appear to differ from the normal, but the 
main feature in the nitrogenous metabolism is the presence in 
the urine, although not in the blood, of a greatly increased quan- 
tity of uric acid. Thus the amount daily excreted in leukemia 
is between 1 and 2 grams (sometimes 4 or 5 grams) so that 
the usual amount is nearly double the normal (0.7). Out of 
eighteen cases of leukemia in which the uric acid was esti- 
mated by various observers (quoted by von Noorden), the 
amount daily excreted was in three cases normal or below the 
normal, and in the remaining cases varied between 0.915 gram 



456 CHANGES IN METABOLISM 

and 1.06 gram. The nitrogenous extractives (xanthin bodies) 
are found increased in the blood and in the urine in many cases. 
The amount of xanthin bodies found is between 6 and 15 eg., 
2 to 3 eg. being the normal amount daily excreted. The in- 
creased quantity of uric acid and xanthin bodies present in the 
urine is due directly to the disintegration of the white cells of 
the blood, their amount being proportional to the number of 
white cells. The substances are derived from the nuclein base 
present in the white corpuscles. 



CHAPTER XIX 

CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

The changes which occur in the nervous system in disease are 
manifold and require special consideration, not only on account 
of the predominating action of the nervous tissue on the other 
tissues of the body, but also because disease processes affect 
the structures in a peculiar manner owing to their anatomical 
and physiological arrangement. The diseases which affect the 
nervous system may be grouped as follows : ( i ) Infections, 

(2) degenerations, whether due to toxic action or inherited, 

(3) gross lesions, such as injury, vascular lesions (hemor- 
rhage and softening), and new growths. It is not, however, 
within the scope of this work to discuss the particular effects 
either of infective processes or of such lesions as tumors of 
the nervous system, but rather to discuss the processes of dis- 
ease of the nervous system; that is, the manner in which dif- 
ferent parts are affected, and their results. 

1. Arrangement of the Nervous System. — The central ner- 
vous system is composed of nerve cells contained in the gray 
matter of the brain and spinal cord, and in the spinal ganglia 
(ganglia of the posterior roots), and of projections from these 
cells which are in physiological, but not anatomical, connec- 
tion with other cells. 

The nervous system is, therefore, composed of cells and 
branches called a neuron, which is anatomically distinct, but 
is physiologically connected with other neurons. The arrange- 
ment of the neurons is shown in the diagram (Fig. in). 
Broadly speaking, they are arranged in two different series or 
projection systems, as they are called : one, efferent or motor, 
the other afferent or sensory. 

457 



458 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 



Pyramid 

Cortex 

Cell \ *$&£&£ J*\ 



Corpus 
Striatum 




erebellar System- 



Nuclei of 
" "Posterior Horn- 



Cell of Clarke's Column 



Stfirtal Ganglion Celf 



Multipolar 

cell of Anterior 

Horn 



Skin 



Fig. hi. — Diagram to show the three systems of neurons, illustrating 
the path of sensory (yellow) impulses to the cerebrum and cerebellum, the- 
path of outgoing (red) impulses from the brain in a voluntary movement, 
and the association of the afferent and efferent projection systems in the 
gray matter of the brain. The path of a simple spinal reflex is shown by 
the dotted line. (F. W. Mott.) 



PROJECTION SYSTEMS OF NEURONS 459 

Efferent Projection System of Neurons. — The efferent neu- 
Ton is divided into an upper motor neuron, starting in the cor- 
tex, and a lower motor neuron, starting in the multipolar cells of 
the anterior cornua of the spinal cord. Commencing in the 
pyramidal cells of the Rolandic area of the cortex, there are 
first the branches of the cell, which connect it with other con- 
volutions, namely, the association fibers. The axis cylinder or 
axon passes from the cell, and gives off in its passage through 
the brain (through the internal capsule and the tegmentum), 
branches which pass into the corpus callosum — commissural 
fibers — which terminate by breaking up into smaller branches 
(arborizations) in the cortex of the other hemisphere. Other 
branches pass to the corpus striatum; while the main branch 
passes to the medulla, and most of it crosses into the cord on 
the opposite side (crossed pyramidal tract), while some passes 
down the cord on the same side (direct pyramidal tract). The 
axis cylinder ends by breaking up into arborizations round the 
branches of the cells of the anterior horns. The upper motor 
neuron, although an anatomical entity, has by its branches 
numerous connections with the cells of other parts of the cortex 
of each hemisphere and with the corpus striatum, as well as 
with the cells of the lower motor neuron. The lower motor 
neuron arises in the multipolar cell of the anterior horn. The 
branches of this cell are in physiological connection with the 
terminations of the axis cylinder of the upper motor neuron, 
and with the cells of the posterior horns of the cord. The axis 
cylinder passes to the muscle. The cell of the lower motor 
neuron is also in physiological connection with fibers passing 
from the cerebellum above. 

Afferent Neuron. — The afferent neurons are more com- 
plicated than the motor. The lowest afferent or sensory 
neuron commences in the nerve cell of the spinal ganglion. 
The axis cylinder from this bifurcates, one part passing to 
the skin and tendon as a sensory nerve fiber, and the other 
passing into the cord, where it has very numerous connections. 
After it enters the cord it passes upwards and is connected by 
means of collateral branches and arborizations with the motor 
cells of the anterior horn, with the cells of the posterior horn 



460 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

and with the cells of Clarke's column. The axis cylinder sends 
branches upwards in the direct cerebellar tract, and is physio- 
logically connected with the cerebellum. The main part of the 
axis cylinder of the spinal ganglion cell passes upwards in the 
cord to the nucleus gracilis and nucleus cuneatus of the 
medulla, where it ends in arborizations in physiological con- 
nection with the nerve cells of the nuclei. The axis cylinders 
of the cells of the nucleus gracilis pass upwards on either side 
of the brain, and terminate round a cell of the optic thalamus. 
The axis cylinder from the cell of the optic thalamus passes 
upwards, and ends in arborizations round the branches of the 
cells of the cortical gray matter, as well as round the branches 
of the motor pyramidal cell. The sensory fibers in the cord 
are, therefore, mainly exogenous. A small tract, called the 
"comma" tract (Fig. 116), is probably endogenous, arising 
from the cells of the gray matter and passing downwards. 

It is obvious from the above description that, although the 
arrangement of the nervous system is conveniently divided 

into efferent or motor, and afferent or 
sensory, systems, yet the arrangement 
is an extremely complicated one, more 
particularly on the sensory side, and 
that this complexity is still further in- 
creased by the consideration of the 
higher functions of the brain, such as 
those comprised in ideation and psy- 
chomotor activity. 

The Nerve Cell. — The structure of 

Fig. ii2.— Normal pyram- the nerve cell is that of a protoplasmic 

^brt'stai^d' b y ° r the <*11, with a large oval nucleus and 

Nissl method, x 700. nucleolus situated in the center of the 

The Nissl granules are jj ,p. n Th jj • divided 

seen occupying the body . l \ L l S- u/ ^ x uc cc | x 1& U1V1UCU 

of the cell and extending into two parts, one of which, forming 
TRW^Mott" processes - the body of the cell (the so-called 
trophoplasm), is continued directly 
into the axis cylinder. Round the nucleus, and continued into 
the branches, there can be demonstrated by appropriate stain- 
ing by methylene blue, certain bodies called Nissl bodies or 




NUTRITION OF THE NEURONS 461 

granules, sometimes referred to as kinetoplasm. These gran- 
ules are composed, in all probability, of nucleo-proteid, inas- 
much as they contain phosphorus and are not digested by pepsin. 
The axis cylinder, composed of protoplasm, is covered, in the 
brain and spinal cord, by a myelin sheath, which consists of 
phosphorized fat. Outside the brain and the cord the myelin 
sheath is still further covered by 'the nucleated sheath of 
Schwann, which is continued in the peripheral nerves. The 
myelin sheath is developed after the axis cylinder, but its 
physiological relation to the axis cylinder is not understood. 
The cellular sheath of Schwann is formed of mesoblastic cells 
and plays some active part in the regeneration of nerves. 

II. Conditions of Nutrition of the Neurons. — A nerve cell, 
after it has undergone a certain degree of degeneration, cannot 
be regenerated, as is the case with other cells. Owing, how- 
ver, to the individuality of the nerve cell and its branches 
(the neuron), the cell once dead cannot be replaced. The axis 
cylinder can, however, be regenerated if one part of it is de- 
stroyed, if the nerve cell is still intact. The duration of life 
of the nerve cell becomes, therefore, of great importance in 
the study of the general pathology of nerve disease, not only 
its inherent vitality, but its vitality as affected by inheritance, 
by the action of poisons, and by the conditions of circulation 
of the blood and of its composition. 

The earliest change which is seen when the nerve cell under- 
goes degeneration is the disapparance, either partial or com- 
plete, of the Nissl bodies, as definite bodies stained by methy- 
lene blue. This is referred to as chromatolysis (Figs. 113 and 
114). Sometimes the granules appear to be diffused through 
the protoplasm of the cell in fine particles. They may disappear 
altogether, a cell being diffusely stained by the reagent. This, 
according to recent research, may be considered as the first 
effect of injury to the nerve cell, and if it is correct to consider 
the granules as consisting of nucleo-proteid, chromatolysis 
must be considered a great change, considering the important 
relation that nucleo-proteid has to the nutrition of the cell, 
and its importance in other pathological conditions (p. 331). 
It is considered that a condition of chromatolysis may be 



462 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 



recovered from. More advanced degeneration of the nerve 
cell is seen in the contraction and distortion of its branches, 
in vacuolation of the protoplasm, the nucleus occupying a 







Fig. 113. — Degeneration in nerve cells, stained by the Nissl method. 

(F. W. Mott.) 

1. Pyramidal cortical cell from a monkey five days after ligature of two 
carotids and one vertebral, showing swelling of the cell with diffuse homo- 
geneous staining, owing to the stainable substance being scattered through 
the protoplasm of the cell as a fine dust. 

2. Pyramidal cell of a dog after ligature of two carotids, one vertebral and 
one subclavian. There is great swelling of the nucleus, and advanced chro- 
matolysis most marked at the periphery of the cell. 

3. A cortical pyramidal cell in acute suffering, produced by ligature of the 
cerebral arteries. The cell is dead and phagocytes are adherent to it. 

4. Spinal motor cell of rabbit, acute botulin poisoning. Swelling of nucleus, 
commencing chromatolysis. 

5. Spinal motor cell from a case of negro lethargy with hyperpyrexia. The 
Nissl granules have disappeared and the staining is diffuse. 



peripheral position and even being extruded. From such a 
condition the nerve cell does not recover. 

(a) It is an important fact that the nerve cell may be 



CHROMATOLYSIS 



463 



affected by an injury to its axis cylinder. Besides the changes 
in the portion of axis cylinder which is severed from the 
nerve cell and which will be described later, there is, so to 
speak, a reaction backwards on the cell itself, and this is shown 






■<■-.: 




Fig. 114. — Degeneration of the cells of the anterior horn of the 
lumbo-sacral enlargement in a case of alcoholic paraplegia. 
(F. W. Mott.) 

1. Shows commencing chromatolysis; disappearance of the Nissl 
granules. 

2. Shows advanced chromatolysis, and the eccentric position of the 
nucleus. 

3. Shows chromatolysis as well as a concavity at one side, indicating 
rupture of the nuclear membrane and death of the cell. 

4. Shows swellingand eccentric position of the nucleus, and extensive 
vacuolation of the protoplasm of the cell, indicating death. 



by chromatolysis and by a displacement of the nucleus 
towards the periphery of the cell. This change does not 
persist in experimental cases, but reparation takes place, the 
nucleus coming back to the center of the cell and the Nissl 
granules reappearing. If, however, the injury to the axis 
cylinder be great, such as when the portion of the nerve is 



464 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

cut or torn away, the cell of origin undergoes degeneration 
and atrophy occurs. 

(b) The nerve cell is also directly affected by poisons — 
chemical, bacterial, and those developed in the body, as in auto- 
intoxication. Thus, in strychnin poisoning and in tetanus, 
there is chromatolysis with the diffusion of the Nissl bodies 
throughout the cell. The cell becomes enlarged, probably 
by hydration, and there are enlargement and pallor of the 
nucleus. Chromatolysis is also observed as the result of the 
action of abrin, ricin, the toxin of the bacillus botulinus, of 
rabies, pellagra, lathyrism, and ergotism. This change is also 
observed in artificially produced hyperthermia, if the tempera- 
ture of the animal, for example, is raised to 109.5 or over. 
There is swelling of the cell and its branches, a diffused stain- 
ing by methylene blue and an irregular nucleus. In some cases 
of hyperpyrexia in man, a similar change is observed. 

(c) The nutrition of the nerve cell depends to some extent 
on its systematic activity. Disuse may lead to degeneration, 
and degeneration or interference with the functional activity 
of one system produces an effect on the functional activity 
of another. An illustration of the first point may be seen in the 
results of the changes following amputation of a limb. The 
long disuse of the nerve which follows in this case leads to its 
atrophy and that of the cells of origin. After amputation of a 
limb, for example, both anterior and posterior roots may be 
found degenerated, as well as the main nerve of the limb. An 
illustration of the second statement is seen in the result of 
dividing the posterior roots. Division of the posterior roots 
from the third cervical to the third dorsal inclusive rendered 
the upper limb insensitive, as was to be expected. But the 
animal was incapable of performing the finer voluntary move- 
ments, showing that the loss of the afferent impulses had 
affected motility, although the efferent path from the cerebral 
cortex, as tested by stimulating it, was normal. Section of 
the posterior roots also causes a loss of tonus in the muscle. 
This interdependence of efferent and afferent systems in the 
performance of normal functions is of great importance in the 
consideration of nervous disease. Section of the posterior 



RESULTS OF INJURY TO THE NEURON 465 

roots may, indeed, cause chromatolysis in the motor cells of 
the anterior horn of the cord. Other examples may be given 
of the effect of injury to one neuron on the functional 
activity of another, or in causing its degeneration; such, 
for example, as the atrophy of the cells of the lower motor 
neuron, when the upper motor neuron is partially destroyed by 
disease, as in hemiplegia. 

III. Anatomical Results of Destruction of a Neuron at One 
or Other Part. — The results which follow destruction of the 
neuron must be considered as to whether the cell is first 
destroyed, or the axis cylinder. 

Injury to the Axis Cylinder. — The effects of injury to the 
axis cylinder have been studied after section of a peripheral 
nerve, of a nerve root, or of the spinal cord itself. Complete 
transverse section of a mixed nerve leads to simultaneous 
degeneration of the nerve fibers below the lesion down to 
their endings — either motor or sensory. Upwards, the nerve 
fibers degenerate as far as the next node. The effect on the 
nerve cell has already been described. The degeneration of 
a nerve below the lesion is spoken of as Wallerian degener- 
ation, and is of the same character whether the axis cylinder 
is severed in a peripheral nerve, in a nerve root, or in the 
brain or spinal cord. The degeneration is characterized by a 
breaking up of the myelin sheath into droplets (Fig. 122), the 
lecithin being decomposed and finally disappearing; while 
the axis cylinder becomes irregularly broken up, and finally 
disappears. Some proliferation of the nuclei of the sheath of 
Schwann occurs. If the two ends of the divided nerve are 
sutured together, regeneration occurs, the axis cylinder grow- 
ing down from the proximal end of the divided nerve and de- 
veloping a myelin sheath. The function of the nerve may in 
time be restored. Section of an anterior root leads to a similar 
Wallerian degeneration below the injury, affecting, however, 
in this case, only the efferent fibers of the mixed nerve. Some 
slight degeneration upwards towards the cord is observed, and 
a change occurs in the nerve cells, but these changes are insig- 
nificant compared to the changes below the lesion. 

Section of the posterior roots has. however, a different effect 
30 



Goll 



466 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

to the foregoing, owing to the entrance of the afferent fibers 
into the cord. By reference to the diagram (Fig. 111) it 
will be seen that section of the posterior root separates the 
axis cylinder from the cell of origin in the spinal ganglion. 
Wallerian degeneration occurs in the part of the root attached 
to the cord, and in the cord along the tracts in which the affer- 
ent fibers run. These tracts are shown in the diagram (Fig. 
1 1 5 ) . The afferent fibers pass up the cord in the posterior col- 
umns : (a) in the column of Goll, the nearest to the posterior 

median fissure; (b) the col- 
umn of Burdach outside 
this; and (c) in one small- 
er column, the tract of Lis- 
sauer, which is between the 
column of Burdach, the apex 
of the posterior horn, and 
the crossed pyramidal tract; 
(d) a fourth tract passes 
down the cord, as the " com- 
ma " tract in the column of 
Burdach. The comma tract 
represents afferent fibers de- 
scending the cord, and when 
it degenerates it is called a 
descending degeneration, in- 
asmuch as it passes down- 




Fig. 115. — Degeneration in the column 

of Goll after section of the pos- 

posterior roots on one side. 

(Kirke's Physiology.) 

The section is taken high up in the cord: 

all the degenerated fibers are seen in the 

column of Goll on the same side. (1) 

Nearest the posterior fissure indicates. 

the degenerated fibers from the lowest 

nerve roots; (2) the degenerated fibers 

from nerve roots higher up in the cord. 



wards. The tract of Lissauer 
is a lateral tract of afferent fibers. The main afferent fibers 
run in the columns of Goll and Burdach, and the parts repre- 
sented in these columns are, starting from the posterior median 
fissure, fibers from the lumbar and sacral regions contained in 
the column of Goll; fibers from the dorsal region, partly in 
the column of Goll and partly in that of Burdach; and fibers 
mainly from the cervical region in the column of Burdach. 
The tracts of degeneration produced by section of the posterior 
nerve roots diminish as they proceed upwards, many of the 
axis cylinders no doubt ending in the cells of the gray matter. 
The degeneration extends upwards as far as the nucleus gra- 



RESULTS OF INJURY TO THE NEURON 



467 



cilis. and nucleus cuneatus in the medulla, which is the termi- 
nation of the lower sensory neuron. 

Section of the spinal cord itself leads to degeneration both 
upwards and downwards, since both afferent and efferent axons 
are separated from their nerve cells. The degenerations which 
occur upwards are those which result from section of the pos- 
terior roots (Figs. 1 16 and 117). Those occurring downwards 
result from separation of the efferent axon from its nerve 
cell : these degenerated tracts are seen in the crossed and 
direct pyramidal tracts. A descending degeneration occurs in 



; Column of Goll. 



Column of Burdach. 
Lissauer's tract. 

Direct ascending 

cerebellar. ? 

Crossed pyramidal. —j—/~~* j ^^W | 
Comma tract. —■'---/ — ~- Trf!-- 1 



Crossed cerebellar 
tract. 

Antero-lateral 
descending. 
Direct pyramidal 
tract. 




Fig. 116 — Section of spinal cord in the cervical region, showing the tracts 
of white matter in one half, and the groups of nerve cells in the other, 
(After Sherrington, from Kirke's Physiology. ) 



the comma tract, which is afferent. Another descending de- 
generation is the descending degeneration of the cerebellar 
tract of the antero-lateral column. Two other ascending tracts 
require to be mentioned : namely, the direct cerebellar tract 
and the antero-lateral ascending tract (Gowers). Both these 
are, as will be seen by reference to the diagram (Fig. in), 
separated from their nerve cell of origin. 

Tracts of degeneration in the brain and spinal cord also re- 
sult from the removal of the cells of origin of the axon. Thus, 
removal of the cortex in the motor area (Rolandic area) results 
in degeneration of the upper motor neuron as far downwards 



468 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 




as the cells of the anterior horns (lower motor neuron). 

tract of degeneration is 

seen in the pyramidal 

tracts of the brain and 

cord. In the cord, both 

the direct pyramidal and 

the crossed pyramidal 

tracts are degenerated. 

Some degenerated fibers 

are found in the lateral 

tract of the cord on the 

same side as the lesion. 

Removal of one lateral 
half of the cerebellum in 
animals leads to degener- 
ation, on the same side, 
of the circumference of 
the antero-lateral column, 
the area of degeneration 
diminishing as it pro- 
ceeds downwards. This 
degeneration probably 
only occurs whenDeiter's 
nucleus is injured or de- 
stroyed. Degenerated 
fibers have also been 
found in the anterior 
roots. 

The functional 
changes which result from 
these degenerations are 
subsequently considered 
(p. 483). Some changes 
concerning the chemistry 
of degeneration must now 
be taken into account. 

IV. Chemical Changes 
Occurring in Nerve Degeneration 



This 



si 









3-S 




"58 

o § « o M 

•r\ tfl .2 s- <& . 

<+-i <U to to ., u-3 <u f 

C £ U c 4> -"-• 5 

2 o §jj.S:*S*J 
o g S*-a«™.o^ 

^'-'Cc^S^g'Oto 



|3 

c a 




-The chemical changes 



CHEMICAL CHANGES IN NERVE DEGENERATION 469 

which occur in degeneration, both of the central nervous system 
and of the peripheral nerves, mainly concern, as far as is known, 
the myelin sheath. This consists, in part, of a substance called 
protagon, which is supposed to be a compound of lecithin and 
cerebrin. Lecithin (C 42 H g4 NP0 9 ) is a complex fat which 
yields, on decomposition, glycerin, stearic acid, phosphoric 
acid, and cholin. The formula for cholin is N . ( CH S ) 3 C 2 H 6 O a 
(p. 73). Some decomposition of protagon probably occurs 
in normal conditions in nerve tissue, but the cholin, which is 
hereby liberated, is not found in the urine and is probably oxi- 
dized in the body. 

That some chemical change occurs in the myelin sheath in 
degeneration, is seen by the reaction of osmic acid, which 
is most conveniently applied to the nerve tissues in the form 
of Marchi's fluid (one part of 1 per cent, osmic acid and two 
parts of Miiller's fluid). The normal nerve fiber, both in and 
outside the central nervous system, stains a light color with 
a greenish tinge by this fluid. When, however, it has degener- 
ated, the myelin, which is mostly in the form of droplets, stains 
a black color just like the reaction of osmic acid on ordinary 
fatty tissue. The change which has probably occurred is there- 
fore the formation of a fat not containing phosphorus. It has 
been found that, in a cord, one-half of which only showed 
degeneration, ether extracted from the degenerated half a 
larger quantity of fat than from the undegenerated ; the 
amount of phosphorus, however, from the degenerated portion 
being less than from the normal. Probably part of the fat 
formed in the process of degeneration comes from the decom- 
position of the proteid of the axis cylinder (Mott). These re- 
sults led to the investigation of the presence of cholin in the 
cerebro-spinal fluid in various forms of degeneration. The 
physiological action of cholin is shown mainly in a fall of ar- 
terial blood pressure, due partly to an action on the heart, but 
mainly to a dilatation of the vessels of the splanchnic or intesti- 
nal area. This action is independent of the influence of the cord 
or splanchnic nerves, as it occurs after section of the cord and 
of these nerves. An extract of brain also produces this result, 
which has been ascribed to the presence of cholin. It may 



47 o CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

therefore be that cholin is a normal result of the metabolism 
of nerve tissue, and that its presence in appreciable quantities 
in degenerated nerve tissue is only an excess of the normal con- 
dition. The cerebro-spinal fluid and blood, in cases of general 
paralysis of the insane, when injected into an animal, cause a 
fall of blood pressure due to cholin (Fig. 118). If atropin is 
injected, there is no fall, but a rise. From the cerebro-spinal 
fluid the cholin has been separated by chemical means. Cholin 




A/^YVVK 



X H V vvuv^ , ^ 



rp 

s. _ 



Fig. 118. — Tracing of intestinal oncometer (I. O.) and arterial blood 
pressure (B.P.) in a cat. T, time; S, signal; A, abscissa. 

Ten cubic centimeters of cerebro-spinal fluid from a case of general paralysis were 
injected. The fall of blood pressure is at first mainly cardiac in origin, for the onco- 
meter tracing first follows the fall of arterial blood pressure passively; it, however, 
soon rises, indicating dilatation of the peripheral vessels. The same effect was pro- 
duced in the same animal by injecting 2 c. cm. of 0.2 per cent, solution of cholin. 
(Mott and Halliburton.) 

has also been found in cases of combined sclerosis, beri-beri, 
and in degenerated peripheral nerves (Mott and Halliburton). 

The cerebro-spinal fluid in general paralysis is also peculiar 
in containing, in some instances, an appreciable quantity of 
nucleo-proteid, which has produced coagulation after intra- 
venous injection into animals. This nucleo-proteid would, no 
doubt, be liberated during the degeneration of the nerve cells. 

Diseases of the Neurons as They Occur in Man. — The dis- 



DISEASES OF THE NEURONS 471 

eases of the neurons as they occur in natural disease in man are 
not so simple as the results observed in experimental lesions 
of the nervous system, the majority of cases of disease being 
due to one or other form of intoxication. The parts of the 
nervous system affected are by no means uniformly the same, 
although certain types of affection may be described. 

The first grouping to be made is into primary and secondary 
degenerations. Secondarv degenerations have practically been 
already discussed. They are due to severance of the axis 
cylinder from its cell of origin. It is thus a Wallerian degener- 
ation, the part of the axis cylinder severed from its cell being 
affected. The secondary degeneration is thus commonly ob- 
served in peripheral neuritis in those fibers in which 
the axis cylinder becomes ruptured. It is also observed in 
transverse lesions of the cord, whether produced by pressure, 
by disease — such as myelitis — or by an injury; and it is 
observed as the result of injury to the efferent fibers of the 
upper motor neurons in the brain, as in hemorrhage and 
thrombosis or embolism of the middle cerebral artery. Tracts 
of degeneration in the spinal cord which result from a trans- 
verse lesion are those which have been described as resulting 
from a section of the cord. The degree of degeneration, how- 
ever, varies in disease according as to whether the lesion is 
completely transverse or only partially so. Again, in the brain, 
the degeneration of the efferent fibers, down as far as the 
lower motor neuron, occurs as the result usually of rupture of 
the fibers, such as occurs in hemorrhage affecting the internal 
capsule or the corona radiata. 

1. Peripheral Neuritis. — There remains for more detailed 
consideration the degeneration which occurs in peripheral 
neuritis. Degeneration of the peripheral nerves due to 
disease is always the result of one or other form of poisoning. 
The commonest causes are chronic alcoholism, plumbism, 
diphtheria, and beri-beri. It may, however, occur as the 
result of the intoxication occurring in influenza, typhoid 
fever, pneumonia, erysipelas, septicemia, malaria, gonorrhea, 
and syphilis, but it is not common after these diseases. It 
occurs in some cases of diabetes, gout, and rheumatism, and 



47 2 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

results from poisoning by arsenic, mercury, phosphorus, and 
silver, among inorganic substances; and ether, carbon disul- 
phid, nitro-benzine, anilin, and carbonic oxid among organic 
substances. 

It is not necessary here to discuss all the conditions pro- 
duced by these various intoxications. The nerve change in 
diphtheria has already been considered (p. 86). A few general 




Fig. 119. — Nerve degeneration in diphtheria (experimental.) 

The figure shows a bundle of nerve fibers in one of the anterior roots 
of a rabbit, paralyzed by the intravenous injection of albumoses from 
the spleen of a patient dead of diphtheria. At one part the nerve fibers 
have lost their white sheath, the primitive sheath and, in some cases, 
the axis cylinder being intact. Stained with osmic acid. 

points in relation to the pathology of peripheral neuritis may, 
however, be mentioned (Figs. 1 19-122). 

(a) In different forms of intoxication, a selective action of 
the poison appears to be evidenced. In chronic plumbism, 
a frequent form of peripheral neuritis, there is an affection 
of certain branches of the musculo-spiral nerve, causing a 
paralysis of the extensors of the hand and dropped wrist; there 
is no affection of the sencory nerves, and the lesion may be 



PERIPHERAL NEURITIS 



473 



symmetrical. In alcoholic neuritis the nerves specially affected 
are those of the extensors of the ankle, causing dropping of 
the foot. Both in lead poisoning and in alcoholism other 
parts may be affected. Thus, in lead poisoning a general 
affection of the nerves may be present, or the nerve cells of 
the brain may be affected, as in encephalopathia saturnina. 
In chronic alcoholism, again, the neuritis may be general, and 
there is a distinct effect frequently on the cells of the spinal 




Fig. i 20— Nerve degeneration in diphtheria (experimental). 

A is a bundle of fibers in the phrenic nerve of a rabbit, paralyzed 
by the intravenous injection of extract of diphtheritic membrane. The 
white sheath is broken up irregularly, and has in part disappeared. In 
one fiber the axis cylinder is seen intact. 

B. Portion of a single nerve fiber from the nerve to the vastus in a 
rabbit paralyzed by the intravenous injection of albumoses from a case 
of diphtheria. There is disappearance of the white substance on each 
side of a node, while the axis cylinder is ruptured and has become 
tortuous. 

Stained with osmic acid. 

cord which show vacuolation and increased pigmentation, as 
well as on the cells of the brain. It is thus evidenced that, 
although the poison may select some particular nerve for its 
action, yet this selection is only part of a general intoxication, 
and is possibly determined by occupation, as, for example, 
occurring in plumbism in the arms of painters and in alcoholic 
neuritis in the legs, which bear more stress than the arms. 

Moderate degrees of neuritis, such as occur in neuritis 
from arsenic medicinally administered, or in diabetes, affect 
the legs more than the other parts of the body; and in 



474 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

rabbits, in which experimental diphtheritic paralysis has been 
produced, the degeneration in the nerves of the muscles of 
the legs is much more marked than in the nerves of the rest 
of the body, more particularly than in those of the forelegs. 

(b) The question arises whether the degeneration of the 
nerve in peripheral neuritis is due to a local toxic action of 
the poison on the nerve fiber, or to a primary effect on the 




Fig. 121. — Nerve degeneration in alcoholic neuritis. 

Three nerve fibers are shown from the nerve to the left tibialis 
anticus. In the uppermost fiber the white substance has disappeared 
from part of the fiber, and the axis cylinder is tortuous and ruptured. 
The second fiber shows a loss of white substance in one part, while the 
third fiber is normal. Stained with osmic acid. 



cell of origin, whereby the trophic influence of the cell on the 
axis cylinder is removed. This point cannot be at present 
decided, but in experimental conditions, more particularly in 
diphtheria, the nerve degeneration appears to be out of all pro- 
portion to any change visible in the cells of origin. In diph- 
theritic paralysis in man, however, changes in the cells are fre- 
quently present, as they are in alcoholic neuritis and in some 
cases of chronic plumbism. 



DISEASES OF THE AFFERENT NEURONS 



475 



(c) The pathological change in peripheral neuritis is mainly 
a degeneration of the nerve fiber, which, after rupture of the 
axis cylinder, leads to Wallerian degeneration below the rupture 
(Figs. 121 and 122). In some cases, however, there is an in- 
crease of connective tissue round the nerve bundles, and this 
is described as a special variety of periph- 
eral neuritis, and called interstitial. It is 
very much open to doubt whether, as some 
appear to believe, this increase of interstitial 
tissue is the cause of the nerve degeneration 
by compression. It is more likely to result 
from the action of the poison itself, which 
produces the nerve degeneration. 

2. Diseases of the Efferent Projection 
System of Neurons. — The diseases here to 
foe considered are those in which the axons 
of the upper efferent neuron are affected, 
as in spastic paraplegia (primary lateral 
sclerosis); those in which these axons are 
affected as well as the cells of origin (amyo- 
trophic lateral sclerosis) — both these lesions 
are, however, mixed, more than one system 
Deing affected; and those in which the 
cells of origin of the efferent neuron are 
affected, such as acute and chronic anterior 
poliomyelitis and bulbar palsy (mainly 
glosso-labio-laryngeal palsy) ; and polio- 
encephalitis. 

(a) Affection of the Upper Projection 
System of Efferent Neurons. — In spastic 
paraplegia the lesion is mainly in the 
pyramidal tracts of each side, being most 
marked in the lower part of the cord and diminishing upwards. 
The lesion is a degeneration of the axons, and appears to be 
— in some cases, at any rate — associated with changes in the 
nerve cells; indeed, the condition does not appear to differ 
pathologically from the condition in peripheral neuritis. Cases 
do occur in which the nerve cells do not appear affected, but 



til 

1 1 



Fig. 122. — Nerve de- 
generation in alco- 
holic neuritis. 

Three nerve fibers 
form the nerve to the 
right vastus internus. 
The middle fiber shows 
slight breaking up of 
the white substance; 
the other two fibers 
show extensive break- 
ing up with destruction 
of the axis cylinder 
(Wallerian degenera- 
tion). Stained with 
osmic acid. 



476 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

the affection of the nerve cells which occurs in some cases would 
bring the disease pathologi- 
cally in line with amyotro- 
phic lateral sclerosis, which 
is a degeneration of the 
whole of the efferent neu- 
ron system affecting the 
cells of the anterior horns, 
and the lateral columns (the 
direct and crossed pyramidal 
fibers) right up to the motor 
cortex (Fig. 123). The le- 
sion not infrequently com- 
mences in the upper part of 
the cord. It is to be consid- 
ered as a disease in which de- 
generation follows changes 
in the cells of origin in both 
upper and lower efferent 
projection neurons. 

( b ) Affection of the Lower 
Projection System of Effer- 
ent Neurons. — In acute an- 
terior poliomyelitis there is 
a primary effect on the cells 
of the anterior horns, leading 
to their granular degenera- 
tion and then to atrophy. The 
result is degeneration of the 
axons of the cells, which ex- 
tends through the anterior 
roots right down to the 
muscles. This is a simple 
instance of degeneration of 
the whole of the lower effer- 
ent projection neuron. A 
similar affection occurs in 
the cranial motor nerves and is referred to as polio-encephalitis. 




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DISEASES OF THE AFFERENT NEURONS 



477 



The condition, however, in chronic anterior poliomyelitis (pro- 
gressive muscular atrophy) does not appear to be so simple 
(Fig. 124), as some consider that 
besides the degeneration of the 
nerve cells in the anterior horns 
there is some degeneration in the 
lateral columns (Gowers). Many 
observers, however, have found no 
such degeneration, showing that 
the upper efferent neuron is un- 
affected. In the majority of cases 
there is degeneration in the an- 
terior roots, and there are many 
degenerated fibers in the peripheral 
nerves. The muscle fibers undergo 
atrophy, the cross striation being 
retained for a long time. 

The changes in bulbar palsy 
come into line with those described 
in anterior poliomyelitis. In none 
of these conditions is the afferent 
projection system of neurons 
affected. Progressive muscular 
atrophy, bulbar palsy, and amyo- 
trophic lateral sclerosis are closely 
related, if not identical in their 
pathological processes. 

3. Diseases of the Afferent Pro- 
jection System of Neurons. — The 
best example of these is seen in 
tabes dorsalis, which may be de- 
scribed as " a primary progressive 
degeneration of the first afferent 
(sensory) projection system of 
neurons." the change which occurs 
being a degeneration of the pos- 
terior spinal roots and the posterior columns of the spinal cord 
(Fig. 125). The trophic center of the first afferent neuron 




478 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 










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DISEASES OF THE AFFERENT NEURONS 479 

exists in the spinal ganglion. It is noteworthy that in tabes 
no pathological changes have been found in these cells ; so that 
whether the degeneration is dependent on some change in the 
cells or is a primary degeneration of the axons is unknown. In 
tabes there is degeneration not infrequently in the peripheral 
nerves, and changes in the muscle spindles. The posterior 
roots are invariably affected, but the extent of degeneration of 
the axons of the afferent neurons in the cord varies with the 
locality in which the disease commences : (a) In most cases of 
tabes the changes begin at the lower part of the cord and 
extend upwards; (b) in some cases the changes commence in 
the cervical region; and (c)in other cases they are in the brain 
and bulb (Marie). 

The tract of Lissauer (Fig. 116) degenerates early, as 
well as the fibers which terminate round Clarke's column of 
cells. As a rule the disease begins in the lumbar roots, and in 
the cord degeneration is seen in Burdach's and Goll's tracts. 
Fibers which are frequently not degenerated are — Flechsig's 
median oval area, the commissural bundle zone, and the 
posterior external angle of the posterior column. The extent 
and position of the tracts of degeneration in the posterior col- 
umns depend on the nerve roots affected. In the column of 
Goll, for example, the fibers become degenerated, more particu- 
larly if the fifth lumbar and first and second sacral roots are 
diseased. If these roots are not affected the tracts degenerated 
are mainly in Burdach's column. Thus in the rare condition of 
cervical tabes Goll's column remains practically undegenerated. 
Although the main stress of disease falls on the first afferent 
projection system of neurons, yet there is an affection of the 
cerebral nerves and ganglia. Thus there is degeneration of 
the optic nerve, which is followed by an affection of the 
ganglion cells of the retina and a spreading of the degen- 
eration towards the corpora quadrigemina and the internal 
geniculate bodies. The glosso-pharyngeal fibers may be de- 
generated as well as the auditory nerve, and the cells of the 
cerebral cortex may show some slight change. 

All the changes just described as occurring in the brain 
are affections of the afferent neurons. Affection, however, 



480 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

of the efferent neurons in the brain may be present, mainly 
in the nuclei of the oculo-motor nerve, followed by degenera- 
tions in the nerves of the eye muscles and in the nucleus of 
the hypoglossal nerve. These are the chief two motor affec- 
tions which occur in tabes : in some cases, weakness of the 
extensors of the forearms has been observed. Although tabes, 
therefore, is mainly an affection of the afferent neurons in the 
spinal cord, the changes in the brain bring it into line with 
another disease — general paralysis of the insane — in which 
there is extensive disease of the afferent neurons, and to some 
extent of the efferent. 

In ergotism, which is produced by the presence of ergot 
in rye bread, there is an affection of the nervous system in 
which the efferent neurons escape, the sensory nerves being 
affected. In some cases the posterior columns of the cord 
have been found affected, as in tabes dorsalis. The posterior 
root zones are said to be affected in the cases exhibiting most 
pain. 

4. Combined Degenerations or Scleroses. — In the conditions 
to be discussed, the seats of degeneration are not all completely 
worked out, owing possibly to the scarcity of accurately made 
post-mortem examinations. In ataxic paraplegia, there is a 
combined sclerosis of the lateral and posterior columns. The 
lesions in the latter tracts resemble those in tabes dorsalis, 
the posterior roots not being affected, however, to so great 
a degree; but the cross pyramidal tracts are mainly affected 
in the lateral columns and also the direct cerebellar tract. In 
this case, therefore, there is a degeneration of both the afferent 
and efferent projection system of neurons. A subacute com- 
bined degeneration, affecting the same parts as in ataxic para- 
plegia, may occur. It is probably of toxic origin. A similar 
anatomical condition to ataxic paraplegia exists in hereditary 
ataxy (Friedreich's disease). Here the degeneration differs 
from that of tabes in that the posterior nerve roots are less 
affected and Lissauer's tract usually escapes degeneration. 

In pellagra, which results from eating diseased maize, 
mainly in Italy, and in pernicious anemia there is degen- 
eration of the posterior and lateral columns of the cord 



COMBINED SCLEROSES 



481 




Fig. 127. — The diagram represents the relative degeneration of fibers 
and nerve cells of the cerebral cortex in amentia and dementia as com- 
pared to the normal. (F. W. Mott.) 



31 



482 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

associated with atrophy of the motor cells of the anterior 
cornua. 

In syringomyelia, the anatomical basis of the disease is 
a destruction, due to disease, of the gray matter, and to some 
extent of the columns of the cord. This may be associated 
with a dilatation of the central canal of the cord. The result 
of the disease is an effect on the conduction of pain and 
temperature, but not of the sense of touch; while the affection 
of the cells of the cord leads to a degeneration of their axons. 
The chief feature of the disease is, however, the affection of 
sensation. 

In two degenerations of the nervous system there is a wide- 
spread affection of different parts, namely, in insular sclerosis, 
and in general paralysis of the insane. Insular sclerosis is char- 
acterized by the appearance in different parts of the brain and 
spinal cord of areas of degeneration which are focal, so that 
there is interruption or affection of both the afferent and ef- 
ferent tracts. There is also an associated degeneration of the 
peripheral nerves, chiefly of the cranial nerves. It is re- 
marked that these areas of sclerosis give rise to no secondary 
degeneration upwards or downwards, but the cells of origin of 
the neurons are affected, and it is probable that the change is 
primarily a parenchymatous one, the sclerosis being secondary; 
though the opposite view is held. 

In general paralysis of the insane there is widespread 
degeneration of the neurons; not only of the association sys- 
tems in the brain, but of the afferent and efferent neurons of 
the spinal cord. The tangential and commissural fibers and as- 
sociation fibers of the cortex are almost uniformly degenerated, 
and there is general atrophy of the brain, more particularly 
of the frontal and parietal lobes. Atrophy of the cranial 
nerves is also frequently present. The lesions of the spinal 
cord which are observed are degenerations in the lateral and 
posterior columns, or an insular sclerosis. The nerve cells 
of the cortex are degenerated. Nissl granules have disappeared 
and the cells are small and irregular in outline, the branches 
showing distortion. The cells eventually undergo disintegra- 
tion, the nucleus becoming irregular or destroyed. The 



EFFECT OF DISEASES OF EFFERENT NEURONS 483 

peripheral nerves show parenchymatous degeneration, es- 
pecially in the lower extremity, and there are frequently 
degenerative changes in the voluntary muscles, in the 
heart and other viscera of the body. There is no disease 
which produces such widespread degeneration of the nervous 
system as general paralysis of the insane. In some instances 
the early stress of the disease is on the spinal cord, the lesions 
of tabes being first developed. In other cases the first stress is 
on the brain. 

Effect of Disease of the Efferent Projection System of 
Neurons. — 1. Disease of the Lower Projection System. — 
The diseases comprise those affecting the cells of the motor 
nuclei of the brain and of the anterior horns (cells of origin), 
and those affecting the peripheral nerves. 

The effect of disease of the peripheral nerves is only in a 
few cases in disease similar to section of a nerve. If there is 
complete severance of a nerve there is loss of power (paralysis) 
and of sensation in the parts supplied by the nerve. Subse- 
quently the muscles waste and give the reaction of degenera- 
tion. This is an increased excitability to the galvanic current 
and a decreased excitability to the faradic current, the appli- 
cation of which in advanced cases produces no contraction of 
the muscle. Normally, the application of the negative pole 
to the tested part gives a contraction with weak currents when 
the current is closed (cathode closing contraction, C. C. C). 
With stronger currents, there is a contraction with the positive 
pole (anode) on the tested part, when the current is broken (A. 
O. C. ) . With still stronger currents there is an anodal closing 
contraction (A. C. C). In the reaction of degeneration the 
changes that take place are that the anodal closing contraction 
(A. C. C.) becomes more marked than even the C. C. C. ; while 
the cathode opening contraction, which requires in health 
stronger currents than are bearable, becomes more marked than 
the A. O. C. The reaction changes as the disease progresses, and 
in the later stages there is only a sluggish and prolonged response 
to galvanism. Vaso-motor palsy is also observed in the part 
affected. It is noteworthy that if the two ends of the divided 



484 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

nerve be sutured together soon after division regeneration of 
the nerve takes place, with more or less complete return of 
motor power and of sensation. Sensation returns before mo- 
tility. If, however, the suturing does not take place for some 
long time after the division, say for months or years, no re- 
turn of motor power occurs, but the sensation may return, and 
the rapidity with which sensation returns after suturing of the 
ends of the nerve in some of these cases is certainly remarkable. 
The absence of the return of power under the conditions de- 
scribed is to be explained by want of regeneration of the 
efferent axons. Two factors influence the delay or absence of 
a return of motor power. One is, if the muscles are completely 
degenerated, even a regeneration of the axons would not 
cause a return of power. But another factor is the effect on 
the cells of origin after the axon has been divided (p. 462) ; the 
cells of the anterior horn being affected, the diminished nutri- 
tion of the axon delays or prevents its regeneration. 

In peripheral neuritis, as seen in disease, all degrees of 
loss of motor power following the nerve lesion are observed. 
It is not common in such cases to find complete degeneration 
of the nerve. In most cases the degeneration is partial, fibers 
or bundles of fibers being affected and lying amidst normal 
fibers and bundles. There is a paresis of the affected muscles 
without an actual paralysis except in advanced cases; this is 
true of many cases of alcoholic and diphtheria neuritis. The 
muscles supplied by the affected nerve undergo fatty degenera- 
tion, usually only in proportion to the degree of nerve degenera- 
tion, and the reaction of degeneration is observed if the 
nerve-muscle is extensively affected. The knee jerks are lost, 
owing to the affection of the reflex arc. There is sometimes 
vaso-motor palsy. The loss of sensation varies considerably. 
It is never so extensive as in primary affection of the sensory 
projection system of neurons, but is usually patchy and shown 
by loss of tactile sensibility in various parts, almost exclusively 
the distal, the trunk usually ascaping. 

Affection of the cells of origin of the lower projection sys- 
tem of efferent neurons leads to paralysis of the musclesj their 
flaccidity, to a loss of knee jerk on the side affected, to the 






EFFECT OF DISEASES OF EFFERENT NEURONS 485 

reaction of degeneration and to a vaso-motor palsy. No 
further comments need be made on these points. The effect, 
however, varies somewhat as to whether the disease occurs in 
children during the growing period or in adults. Thus in 
infantile palsy, in addition to the changes already described, 
there is an arrest in growth of the part affected, an arrest 
which affects all the tissues of the limb, including the bone 
and joints. This arrest of growth has been ascribed to a 
trophic influence, but this is a question somewhat difficult to 
decide. It has been said that the cells of the anterior horns 
exercise a trophic influence over the tissues of the limb which 
is supplied by nerves from them, but it may be that the defect- 
ive nutrition shown in arrested growth — or rather diminished 
growth — is due to the paralysis, that is, to the absence of the 
contraction of muscles and to the altered blood supply due to 
the vaso-motor paralysis. 

In anterior poliomyelitis occurring in adults, these trophic 
changes are not observed. The change in progressive muscular 
atrophy (degeneration of the anterior horn cells) differs from 
that in infantile palsy, from the fact that the muscles do not 
show a typical reaction of degeneration. This is, however, 
present in a modified form in many cases. 

2. Effect of Disease of the Upper Projection System. — The 
result of degeneration of the axons of the cells of origin of the 
upper motor neuron is the production of paresis or paralysis of 
the part and wasting of the muscles from disuse. No reaction 
of degeneration occurs, but there is a diminished excitability of 
the muscular tissue to electrical stimulation. Vaso-motor palsy 
occurs, but the main results besides the paresis of muscles are 
spasm and contracture of the affected part, and an increase 
of the knee jerks. Increase of the knee jerks is due to the 
fact that, the normal inhibitory influence of the brain being 
removed, the reflex arc associated with the knee jerks becomes 
more excitable. 

The explanation of the spasm which occurs mainly in spastic 
paraplegia, but also in secondary degeneration following 
hemiplegia, is not so simple, and still awaits elucidation. 
In spastic paraplegia the development of the spasm and 



486 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

spastic gait is a very slow process, and, although present when 
the individual is quiescent, the spasm is increased and fre- 
quently brought out by a voluntary movement. It has been as- 
cribed to the removal of inhibition from the cerebral centers 
which normally have an inhibitory influence on reflex move- 
ment. This would mean that volitional impulses passing from 
the cortex in a case of spastic paraplegia would be imperfectly 
conducted down the pyramidal tracts, down some of the axons 
not at all owing to their degeneration, and that more powerful 
impulses than normal, passing down the unaffected axons, 
would stimulate the cells of origin of the lower motor neuron 
to an exaggerated effect on the muscles. This, however, is a 
purely theoretical consideration, and is not supported by any ex- 
perimental or pathological evidence. Another explanation of 
spasm is that it is due to a reaction of the cerebellum which 
normally exercises a tonic influence on the muscles, the axons 
of cells in the cerebellum being in relation with the cells of the 
anterior horns. In spastic paraplegia, the influence of the 
cerebral centers being removed or diminished, there is over- 
action on the part of the cerebellum leading to increased tonus 
of the muscles, resulting in spasm. 

Affection of the cells of origin of the upper motor neuron 
leads to very varying results, as is seen in disease of the cortex. 
Destruction of the cells leads to palsy of the parts supplied 
from the cells, with some slight . degree of loss of sensation. 
There is no reaction of degeneration, but wasting of the 
muscles may be observed, mainly from disuse. Irritation of 
the cells leading to increased activity also occurs, leading to 
impulsive movements of varying kinds (p. 490). In amentia 
and dementia there is degeneration of the cells and the fibers 
in varying degree. This is shown in Fig. 127. 

Effect of Disease of the Afferent (Sensory) Projection 
System of Neurons. — Sensation is affected by interruption in 
any part of the path of afferent impulses. The degree, how- 
ever, of affection varies in individual diseases. 

In disease of the peripheral nerves the loss of sensation is 
not complete, except in the case of severance of the nerve. In 



EFFECT OF DISEASES OF AFFERENT NEURONS 487 

peripheral neuritis in which a mixed nerve is affected, sen- 
sation may not be affected, and when affected, the loss is not 
complete. Affection of sensation is seen in numbness and 
tingling and in the loss of tactile sensibility. 

A profound affection of sensation occurs in tabes dorsalis 
and in other affections in which the posterior columns of the 
cord are affected, as well as in syringomyelia in which the 
gray matter of the cord is affected, and in some cases the 
posterior columns. In tabes dorsalis, the loss of sensation is 
over the part supplied from the affected area of the cord and 
posterior root. There is loss of tactile sensibility or delayed 
sensation of touch, a loss of sensation to pain as well as 
loss of sensation of heat and cold. In addition, there is a loss 
of muscular sense; that is, a loss of co-ordination, so that 
the individual walks with his eyes on his feet, cannot walk 
in the dark, and sways in the upright position with the eyes 
closed (Romberg's sign). The gait is ataxic; hence the name 
of the disease — locomotor ataxy. In syringomyelia, there is 
loss of sensation which is of a peculiar and characteristic kind. 
Over the parts affected there is loss of sensation to pain and 
to temperature, while tactile sensibility is retained, and this 
is the chief condition in which this combination of results 
obtains. It may occur in other central lesions of the cord: 
but these are rare. 

It is in tabes and syringomyelia that trophic changes, or 
trophoneuroses, occur with more frequency than in any other 
nerve condition. They also occur in general paralysis of the 
insane, but only when tabes coexists with it. In tabes, there 
is an affection of the bones which leads to their spontaneous 
fracture, more particularly of the long bones and those of the 
limb affected by the disease. The bony tissue is worm-eaten 
and atrophied, new tissue in some cases being deposited round 
the articular edge of the bones. The inorganic elements of 
the bones, more particularly the phosphates, are diminished 
from 66 to 24 per cent., while the organic are increased from 
33 to 76 per cent. Atrophy of the bones occurs also in old 
age and in malignant disease, but this is probably a result due 
to a general defect of nutrition, whereas in tabes the bones 



4 88 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

affected are those of the limb showing the signs of the nerve 
disease. It is the same case with a joint disease (Charcot's 
disease), which is mainly an atrophy of the heads of the bones 
and the cartilage, with an increased secretion of thin fluid some- 
what like synovia. Osteophyte growths are not uncommon 
round the edge of the bone, and are possibly not a part of the 
trophic disease, but are the result of irritation produced by 
moving the joint. The vertebral column is also affected, and 
the foot. The tabetic foot has a truncated appearance, like that 
of a Chinese lady. The arch has disappeared, and the con- 
dition appears to be due to atrophy of the bones of the foot. 
In syringomyelia, similar trophic changes occur in the bones 
and joints, but they are more common than in tabes. Scoliosis 
is a common symptom. Perforating ulcer of the foot is more 
common than in tabes, Friedreich's disease, or in other nerve 
conditions, although it may occur as a sequel of compression 
of the nerves and spinal cord, of injury to the nervous system 
and of peripheral neuritis. The trophic changes which are 
observed in tabes and in syringomyelia are clearly associated 
with an affection of the sensory tract; but whether they are 
due to an affection of trophic centers, or where these are 
situated, is as yet unknown. It is possible that the nerve 
cells, associated with trophic changes, are in the gray matter 
along the whole length of the cord, and that there are no 
definite centers, such as exist for other actions in the medulla 
oblongata. It has been suggested that the trophic changes 
are associated with paralysis of the vaso-motor nerves or 
centers, a suggestion which it is impossible to reconcile with 
the extreme damage which occurs in a Charcot's joint. It 
has also been considered that the sensory fibers from an 
articulation form a reflex arc through the vaso-motor center 
with the vaso-motor nerve fibers, and that the atrophy of 
the bone and joint is due to irregularity of the impulses 
transmitted through the bone and articulation, whereby a de- 
ficient nutrition is produced, and so atrophy. 

Other trophic lesions are observed in diseases of the nervous 
system. Thus, following injury to nerves, an affection of the 
joints of the part is described, which may begin with effusion, 



TREMOR 489 

but passes on to stiffness of the joints and to fibrous anchy- 
losis. Wounds of nerves are followed in some instances by a 
glossy skin over the part affected, red blotches occurring in the 
skin as well. Pemphigus also sometimes follows injury to 
nerves. 

Herpes zoster is an eruption of the skin following the dis- 
tribution of nerves, which is accompanied by great pain, and 
is associated with acute disease of the spinal ganglion. 

Besides the effects which have been already described as 
resulting from disease of one or other part of the projection 
systems of neurons, there remain for consideration certain 
special effects observed as the result of disease mainly of nerve 
cells. These are tremor, spasm, and convulsions. 

Tremor. — Tremors are to-and-fro movements of the limbs 
and of the head and neck which occur in very various condi- 
tions. They are observed in specific diseases of the nervous 
system, such as paralysis agitans, disseminated sclerosis, and 
general paralysis of the insane. In the first case the hands 
are affected more particularly; in the second the parts are 
those affected by the sclerosis, more particularly the hands 
and arms, the head and neck and the ocular muscles (nystag- 
mus); while in general paralysis tremor affects not only the 
facial muscles, but the hands. Tremor is also observed in 
the hands in Graves' disease, in the hands and head in old 
age (senile tremor), and, more particularly in the arms, as 
the result of poisoning by/ alcohol and mercury, and in con- 
valescence from acute disease. It also occurs as the result of 
shock and fright. 

Tremor may be spontaneous and continuous, as in paralysis 
agitans, and also in senile, alcoholic, and mercurial tremor. As 
a rule, however, even if not initiated, tremor is exaggerated by 
voluntary movement, more particularly in disseminated scle- 
rosis, mercurial tremor, and Graves' disease. The part of the 
nervous system affected in tremor is the nerve cell or center. 
Disease of the efferent nerve does not lead to tremor. The 
afferent nerve acts as a conductor of impulses in tremor due to 
shock or fright. This may be called reflex tremor. 

Tremor is due to an irregular discharge from the nerve cell 



49 o CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

to the muscles in conditions in which the vitality of the nerve 
cell is diminished, as in general paralysis, alcholic poisoning, 
and in the convalescence from acute disease. The rate of 
tremor varies. The movements occur three to seven times per 
second in paralysis agitans, and are rather more frequent in 
disseminated sclerosis and alcoholic tremor. 

Spasm and Convulsions. — One form of spasm, namely, that 
associated with degeneration of the pyramidal tracts, has al- 
ready been considered. In this case the spasm is associated 
with removal of the influence of the cells of the upper efferent 
neuron on the cells of the lower motor neuron. This spasm' 
is tonic, that is, produced by a slow and prolonged contraction 
of the muscles. Spasm may also be clonic; that is, produced 
by a rapid contraction and relaxation of the muscles. Tonic 
and clonic spasms are produced by a direct effect on the motor 
nerve cell of the upper or lower efferent neuron, either by a 
direct effect on these cells or by a reflex effect. A direct effect 
on the cells is observed in certain special diseases such as epi- 
lepsy, hysterical convulsions, puerperal and renal eclampsia,, 
toxic convulsions, and asphyxial convulsions. 

In epilepsy there is a period of tonic spasm, followed by 
clonic spasms, due to the discharges from the cortical motor 
cells. These discharges are recurrent, producing the epileptic 
fits. In hysterical convulsions similar cortical discharges oc- 
cur, but they are more irregular. Convulsions due to renal or 
puerperal conditions are possibly due to the effect of some 
poison on the nerve cell, although they may be associated with 
an altered cerebral circulation. In asphyxia, convulsions are 
due to the effect of a deficiency of oxygen and an excess of 
carbonic acid on the nerve cell, while a definite toxic effect 
on the nerve cell is observed in strychnin and picrotoxin 
poisoning, in tetanus, and in infective disease in children. In 
the first three cases the convulsions are mainly of spinal cord 
origin. 

Reflex convulsions occur mainly in children, and are ob- 
served in rickets and in intestinal disturbances, whether due to 
the indigestion of food or to the presence of worms. 

Spasms due to mechanical irritation of the cells occur 



EFFECT OF CIRCULATORY CHANGES 491 

mainly from pressure on the cortex, or as the result of some 
local inflammation. 

Effect of Changes in the Circulation on the Brain and 
Spinal Cord. — The conditions of circulation of blood in the 
brain have certain peculiarities which it is necessary to discuss 
separately, and which bear a distinct relation to certain nervous 
diseases. The arteries in the brain and spinal cord are end- 
arteries ; that is, are vessels whose branches do not anastomose 
with those of neighboring arteries, but break up into capil- 
laries continued into the veins. There is no evidence that the 
arteries have vaso-motor nerves, and it appears that in the brain 
at any rate, the cerebral circulation " passively follows the 
changes in the general arterial and venous pressure." A rise 
of general arterial pressure accelerates the flow of blood 
through the brain, and a fall slackens it. Increase of pressure 
in the vena cava would, therefore, impede the cerebral circu- 
lation. The brain, however, is not passively supplied by blood 
according to the conditions of the general circulation, inasmuch 
as the supply of blood is controlled by centers in the medulla. 
When more blood is required, the heart is accelerated and the 
pressure in the carotid artery raised. The influence of gravity 
is counteracted by means of an increase in the cardiac beat and 
by the general vaso-motor mechanism. If, as in some cases of 
disease, such as shock and exhausting disease, there is weak 
action of the heart and a paralysis of the vaso-constrictor 
mechanism, the influence of gravity leads to a collection of 
the blood in the great abdominal veins, and diminution or 
cessation of the circulation in the brain, thus leading to syn- 
cope. Leonard Hill considers that hyperemia of the brain 
does not exist as a pathological state. Anemia of the brain 
is, however, observed, and has already been partly discussed 
in the discussion on Cheyne-Stokes respiration (p. 289). 
Local anemia of the brain is produced by embolism (p. 348), 
and results in disease of the cerebral tissue. The subject of ane- 
mia of the brain has been studied experimentally by embolic oc- 
clusion of the arteries, or by ligature of the cerebral arteries. 
The effect of the production of anemia of the whole of the 



49 2 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

brain leads to loss of consciousness and a general motor paral- 
ysis; sometimes with epileptiform convulsions, dilatation of 
the pupils, and nystagmus. The muscles become rigid and 
there is hyperexcitability. Ligature of the four cerebral ar- 
teries in cats and monkeys leads to tonic spasm, and if 
after this operation absinthe be injected, there is an increase 
of the spasm, instead of the usual effect of the production of 
clonic spasms. In dogs recovery takes place after ligature of 
all the four arteries (that is, both carotids and both verte- 
brals) owing to the fact that a collateral circulation is estab- 
lished through the superior intercostal artery and the an- 
terior spinal artery. For some days, however, the dogs remain 
paretic and demented, and in this condition the nerve cells 
show distinct changes, such as the loss of the Nissl granules 
and the swelling of the cell as well as of the nucleus, which 
may become eccentric or may even be extruded (Fig. 113). 
The conditions of circulation in the brain may, to some ex- 
tent, explain the loss of consciousness which occurs in syncope 
and in epilepsy. In animals in which no collateral circulation 
is established after ligature of the cerebral arteries, the nerve 
cells degenerate, showing a diffused staining by the Nissl 
method and destruction of the processes of the cells. 

The spinal cord is also sensitive to alterations in the amount 
of blood supplied to it. Thus, if the abdominal aorta be com- 
pressed from one-quarter to three-quarters of an hour, a 
temporary paraplegia occurs, which disappears when the 
circulation is restored. If, however, the compression of the 
aorta lasts for one hour or more the paraplegia is permanent, 
and an examination shows that the cells of the gray matter 
are affected, chromatolysis occurring with atrophy of the 
nucleus, while those tracts of the cord in direct connec- 
tion with the gray matter degenerate, the pyramidal tracts 
and the afferent tracts coming from the spinal ganglion not 
being affected. 

Causation of Degeneration of the Nervous System. — 
Local disease of the nervous system or of the surrounding 
parts leads to a local effect, which may be associated with' a de- 
generation of the neurons in the manner already described. 



CAUSES OF DEGENERATION 493 

Degeneration of one or other part of the nervous system, apart 
from local disease, also occurs, and the causation of this must 
be briefly considered. It is a wide subject, which includes the 
changes occurring in insanity as well as in primary degenera- 
tion of the neurons. The causes of these changes are still a 
matter of discussion, but a prime position in the consideration 
of their causation must be ascribed to heredity; and it may be 
said that diseases of the nervous system are the chief diseases 
of the body in which heredity plays a prominent part. This 
is seen, for example, in the inheritance of insanity, of epilepsy, 
of neuroses such as migraine and asthma, and in the inherit- 
ance and in the occurrence in families of such diseases as 
Friedreich's ataxy. But heredity plays a still further part in 
the predisposing to nervous disease, inasmuch as the inherit- 
ance of nerve conditions is not only interchangeable, but, in 
an apparently normal individual with a nerve history, a disease 
other than that of the nervous system will bring out the hered- 
itary defect, as is seen, for example, in epilepsy, in puerperal 
mania, and in many other forms of insanity. An infective dis- 
ease is frequently the initiating cause as, for example, scarlet 
fever in epilepsy and typhoid fever and influenza in mental de- 
rangement. A second great predisposing or initiating cause 
of nerve disease and degeneration is toxic, and besides the dis- 
eases already mentioned, such as ergotism, pellagra, and 
lathyrism, which are due to specific causes, the two poisons 
which are most frequently concerned in the production of 
nerve disease are alcohol and syphilis. The effect of an excess 
of alcohol is seen first in blunting of the intellectual faculties, 
the production of emotional disturbances, and the production 
of inco-ordination of movement — effects which are quite sep- 
arate from the causation of alcoholic neuritis, or the effect of 
the poison on the internal organs. Syphilis is a disease which 
affects the nervous system in three different ways — gummata 
are formed; arteries may become diseased; and, without either 
of these specific lesions, degeneration of the neurons may occur, 
as in tabes dorsalis and general paralysis of the insane. 

What other poisons may act in producing disease of the 
nervous svstem is not known, but it is evident that some of the 



1 



494 CHANGES IN THE NERVOUS SYSTEM IN DISEASE 

diseases of the central nervous system are infective in origin; 
either a primary infection, or secondary to some general infec- 
tion or intoxication. These diseases more particularly are 
acute anterior poliomyelitis, acute polio-encephalitis, and acute 
myelitis not due to pressure. An affection of the peripheral 
nerves is due in the vast majority of instances to one or other 
form of intoxication (p. 471). 

The question of the tissue immediately and primarily af- 
fected in many chronic diseases of the nervous system is one 
in which it is very difficult to arrive at definite conclusions. In 
many of these diseases, there is, in addition to degeneration of 
the nerve elements themselves, sclerosis of the tissue around 
(the neuroglia), as well as, in many, disease of the vessels in 
the perivascular spaces of the brain. The question arises, 
which of these changes, the nerve degeneration, the sclerosis, 
or the vascular changes, is the primary? Modern research 
tends to the conclusion that the nerve degeneration is the pri- 
mary change, the other lesions being subsidiary. There is, for 
example, no reason why, if the sclerosis were primary it should 
affect a definite tract in the nervous system; and the same re- 
mark applies to any vascular changes. Sclerosis, like fibrosis 
(p. 220), arises from irritation, and it is a question whether 
it arises from the poison producing the nerve degeneration or 
from the chemical products of the nerve degeneration (p. 
468) . This cannot at present be decided : but it may be pointed 
out that the virus of syphilis and alcohol are common causes of 
fibrosis elsewhere in the body. In some instances vascular de- 
generation and sclerosis appear to go pari passu with the nerve 
lesion. 

The Effect of Nerve Disease on the Body and on Metab- 
olism. — In all cases of prolonged disease of the nervous 
system there is an effect on the general nutrition. This is as- 
sociated not only with fatty degeneration and infiltration of the 
heart, but with a similar change in the liver, and sometimes in 
the voluntary muscles, more particularly of the diaphragm. 
Individuals with chronic nerve disease are predisposed to the 
invasion of infective micro-organisms, and death not uncom- 
monly occurs from such causes, either, in paralysis of the blad- 



GENERAL CHANGES IN NERVOUS DISEASE 495 

der, from cystitis leading to pyelitis and pyonephrosis; by an 
infected bed sore of a paralyzed part; or, more generally, by an 
infection of the lungs. 

In conditions in which there is a generalized paralysis of 
muscles, the nutrition of the whole body suffers. This is 
readily understood when it is considered how large a part the 
muscles play in the general metabolism of the body. 






INDEX 



Abrin, action of. 89; immunity by, 
177; necrosis produced by, 217 

Acetic acid fermentation, 70 

Aceto-acetic acid, in diabetes, 447; 
in inanition, 431 ; in pyrexia, 44 

Acetone, in diabetes, 448; in inani- 
tion, 431, in pyrexia, 44 

Acromegaly. 417 

Actinomyces, 52 

Addison's disease, 419 

Agglutinins, 186. 

Albuminoid degeneration, 209 

Albuminuria, causes of, 405 ; in 
pyrexia, 45 

Albumoses, in anthrax, yy ; in 
diphtheria. 79 ; in typhoid fever, 
96 

Albumosuria, causes of, 408; in 
pyrexia, 45 

Alcaptonuria. 405 

Alcoholism, fibrosis of liver in. 
224; in nerve disease. 473, 493 

Alexins, 328 

Amyotrophic lateral sclerosis, 476 

Anemias, condition of blood in, 
303 ; fatty degeneration in, 203 ; 
metabolism in, 453 ; edema in, 
274 ; pernicious, 307 ; primary, 
303 ; respiratory exchange in, 
452 ; secondary, 304 

Angio-sclerosis, 256 

Angina pectoris, causation of. 238 

Anthrax. See B. anthracis 

Antiferments, 179 

Antirennin. 185 

Antitoxins, general characters of, 
179; theory of formation of, 183 

Arteries, dilatation of, 233; influ- 
ence of nervous system on, 232; 
in hemorrhage, 358; local dis- 
eases of, 255 ; causes of disease 
of. 261 



Aspergillus, effects of, 52 
Asphyxia, 293, 360 
Ataxic paraplegia, 480 
Atheroma. See Arteries' 
Atrophy, 212 

Bacillus anthracis, characters of, 

56; chemical products of, 77; 

immunity by, 169, 174; process 

of infection by, 121 
Bacillus botulinus, characters of, 

59: toxin of, 59, 462 
Bacillus coli communis, characters 

of, 58; products of, 99 
Bacillus diphtheria;, characters of, 

56; immunity by, 175; products 

of. 79, 472 
Bacillus enteritidis (Gaertner), 

characters of, 58; products of, 

98 
Bacillus enteritidis sporogenes, 

characters of, 59 
Bacillus mallei, characters of, 57; 

products of, 103 
Bacillus pestis. characters of, 57; 

immunity by, 171 
Bacillus pyocyaneus, characters of, 

58; immunity by, 174, 182 
Bacillus tetani. characters of, 57; 

immunity by, 177; products of, 

91 

Bacillus tuberculosis, characters 
of, 56; distribution of in the 
body, 138; process of infection 
by, 127; products of, 100 

Bacillus typhosus, characters of, 
56; immunity by, 171; micro- 
organisms allied to, 58; process 
of infection by, 112, 141; prod- 
ucts of, 94 ; serum reaction with, 
188 

Bacteria, aerobic and anaerobic, 



.^2 



497 



498 INDEX 



60 ; characters of pathogenic, 55 ; 
effect of nutrient medium on, 
62 ; effect of sunlight on, 61 ; 
fermentation by, 69; mode of 
growth, 60; necrosis by, 220; 
outside the body, 63; products 
of pathogenic, 74; putrefactive, 
71; relation to oxygen, 60; 
variability in virulence of, 65 

Bacteriolysines, 186 
/?-amido-butyric acid, 448 

Bile, secretion in disease, 377 

Bile salts, physiological action of, 
368; secretion in jaundice, 377 

Bilirubin, chemical relations of, 
369 ; in gall-stones, 378 

Blastomycetes, 53 

Blood, changes in corpuscles in 
disease, 298; coagulation — in- 
travascular, 332; fluidity — in- 
ravascular, 333; in bile, 377; in 
kidney disease, 397 ; in urine, 405 

Blood plates, in normal blood, 308 ; 
in thrombosis, 336, 345 

Blood pressure, causes influencing, 
232, 235, 256; in atheroma, 256; 
in hemorrhage, 357; in kidney 
disease, 258, 391 ; maintenance 
of, 257; measurement of, 260 

Body-weight (see also Metab- 
olism), effect of diphtheria toxin 
on, 84 

Botulism. See B. botulinus 

/?-oxy-butyric acid, in diabetes, 
447; in inanition, 431; in pyrexia, 

44 
Bright' s disease. See Kidneys 
Butyric acid fermentation, 70 

Caisson disease, 353 

Carcinoma, effects of, 155; mode 
of spread of, 153 

Caseation, 219 

Cells (see also Nerve cells), 
changes in fatty degeneration 
of, 199; composition of, 194; de- 
generation of, 196; necrosis of, 
214 ; nutriment of, 195 ; secretion 
of, 194 

Charcot's disease, 488 

Chemiotaxis, positive and nega- 
tive, II, 33 

Cheyne-Stokes breathing, 289 

Chlorosis, blood. in, 306; fatty de- 
generation in, 203 ; metabolism 
in, 452 



Cholera. See Vibrio cholerae asia- 
ticse 

Cholelithiasis. See Gall-stones 

Cholesterin, in gall-stones, 379; in 
leukemic blood, 455 

Cholin, from putrefaction, 73; in 
nerve degeneration, 469; physio- 
logical action of, 469 

Chondrogen, 195 

Chromatolysis, 461 

Circulation of blood, coronary, 
237 ; effect of arterial disease on, 
254; effect of disease of heart 
on, 233; effect of disease of 
heart muscle on, 236; effect of 
disease of pericardium on, 234; 
effect of kidney disease on, 258, 
391 ; effect of nervous system 
on, 232; effect of valvular 
lesions on, 242; in brain and 
spinal cord, 491 

Cirrhosis. See Fibrosis 

Cloudy swelling, 196 

Coagulins, 190 

Colloid degeneration, 212 

Color index, 299 

Congestion, mechanical. See Cir- 
culation of Blood 

Conglutination, 336 

Convulsions, 490 

Cough, causation of, 293 

Cyanosis, causes of, 292; metab- 
olism in, 450; respiratory ex- 
change in, 450 

Cystinuria, 400 

Cytases, 192, 328 

Cytotoxins, 190 

Diabetes (see also Glycosuria), 

446 ; coma in, 447 
Diacetic acid. See Aceto-acetic 

acid 
Diapedesis. See Leukocytes 
Diazo-reaction, 45 
Diphtheria. See Bacillus diph- 

theriae 
Degeneration of tissues, causes of, 

193; colloid, 212; dropsical, 212; 

fatty, 197; fibroid (see fibrosis), 

varieties of, 220; Wallerian, 205, 

465, 47i 
Dropsy. See Edema 
Dropsical degeneration, 212 
Dysentery, amebic, 143; bacillus 

of ' 58 . ,• • 

Dyspnea, 279; metabolism in, 450 



INDEX 



499 



Edema, causes of, 269; in disease, 
273 ; inflammatory, 7 ; non-in- 
flammatory, 263 

Effusions, chylous, 265 ; composi- 
tion of. 9 ; inflammatory. 7 ; non- 
inflammatory, 263 ; urea reten- 
tion in. 397 

Embolism, air. 353; fat. etc., 354; 
infective. 125. 352: non-infective, 
345 ; results of. 348 

Endocarditis, infective, action of 
poisons in, 80 ; process of infec- 
tion in, 124 

Enteritis, infective, 146 

Eosinophilia, 313 

Ergotism, 480 

Erythroblasts. 298 

Ethereal hydrogen sulphates, 403 

Fat (see also Obesity), composi- 
tion of. log; metabolism of. 428, 
433, 448 

Fatty degeneration, causes of. 197; 
changes in, 199; in alcoholic 
poisoning, 208 ; in infective dis- 
ease, 208 ; in the nervous system. 
204, 469 

Fatty infiltration, 197 

Ferments, of digestive glands, 195 ; 
bacterial, 69 et scq. 

Fermentation, of non-pathogenic 
bacteria, 69; of pathogenic bac- 
teria, 74 

Fever. See Pyrexia 

Fibrosis, arterio-capillary, 256; 
causes of, 220 ; of special parts, 
224. 494 

Food poisoning, 144 

Friedreich's disease, 480 

Gall-stoxes, 378; mode of for- 
mation. 381 

Gelatin, 195 

General paralysis, 482 

Glanders. See B. mallei 

Glycosuria, caused by suprarenal 
extract, 423 ; caused by thyroid 
extract, 415; experimental, 442; 
in liver disease, 377; in man, 446 

Glycuronic acid. 442 

Gout (see also Uric acid), changes 
in, 439 

Granulation tissue. 21 

Heart (see also Circulation of 
blood), changes in rate and 
force, 248 ; dilatation and hyper- 



trophy of, 239 ; effect of valvular 
lesions, 242; edema in disease 
of, 274 

Heart muscle, changes in fatty de- 
generation of, 199; effect of dis- 
ease of, 236; fatty degeneration 
of, in anthrax, 78; fatty de- 
generation of, in diphtheria, 88; 
fatty degeneration produced by 
typhoid toxin, 95 ; fibrosis of, 
224 

" Heat " centers, yj 

Hematin, 323 

Hematoidin, 364 

Hemoglobin, 323 ; relation to bili- 
rubin in jaundice, 370 

Hemoglobinemia, 325 

Hemoglobinuria, 152, 325; relation 
to jaundice, 374 

Hemolysins, 326; bacterial, 329 

Hemorrhage, causes of, 355; in 
mitral stenosis, 359; in renal 
disease, 358; results of, 363 

Hemosiderin, 364 

Hepatotoxin, 190 

Heterorysins. 329 

Hiccough, 297 

Hydremia, 272 

Hyperpyrexia. 38 

Hypertrophy, of heart muscle, 
241 ; of organs, 230 ; of volun- 
tary muscle, 228 

Hyphomycetes, 51 

Immunity, 157; examples of, 165; 
condition of blood and tissues 
in, 178 

Inanition, 429 

Indican, 405 

Indol compounds, from putrefac- 
tion. 72 ; in urine, 404 

Infarction. 349 

Infection, course of, ti6; ex- 
amples of. 121; mixed, 118; 
modes of. 114; process of, 109 

Inflammation, changes in blood 
stream in, 2 ; changes in blood 
vessels in, 4 ; chronic, 24 ; course 
of, 20; effect of nervous system 
on, 7; effect on tissues, 11 ; exu- 
dation of liquid in, 7; immigra- 
tion of white and red corpuscles 
in, 4, 9; in invertebrata, 27; in 
non-vascular tissues, 24; irri- 
tants causing, 19; repair in, 20; 
varieties of, 12 

Insular sclerosis, 482 



5°o 



INDEX 



Intestines, infection of, 141 
Intoxication, bacterial, 116; in 
nerve disease, 470 et seq.; se- 
quelae of, 121 
Isolysin, 329 

Jaundice, causes of, 368 ; influence 
on metabolism, 375 

Kidney, albuminuria in disease of, 
407; changes in fatty degenera- 
tion of, 199, 208; effect of dis- 
ease on function, 390; fatty de- 
generation in infective disease, 
88, 208; fibrosis of, 226; edema 
in disease of, 275 ; metabolism in 
disease of, 394; regeneration of 
tubules of, 229; results of extir- 
pation of, 387 

Lactic acid, fermentation, 70; in 
pyrexia, 44 ; in liver disease, 384 

Lardacein, 196 

Lecithin, 204, 266, 469 

Leprosy, bacillus in, 56, 113 

Leucocidin, 190 

Leukocytes, immigration in inflam- 
mation, 9; origin of, 319; varie- 
ties of, 308; varieties' of phago- 
cytic, 32 

Leukocytosis, 311 

Leukopenia, 310 

Leukemia, blood in, 315, 455; fatty 
degeneration in, 203; metab- 
olism in, 454 

Liver, acute yellow atrophy of, 
207; changes in fatty degenera- 
tion of, 199; disordered func- 
tions of, 382; cirrhosis, 225; in 
pyrexia, 45; regeneration of 
cells of, 229; results of extirpa- 
tion and disease of, 384 

Lipomatosis. See Obesity 

Lymph, composition of, 263; for- 
mation of, 266 

Lymphemia, 317 

Lymphagogues, 267 

Lymphocytosis, 314 

Macrocytes, 300 

Madura foot. See Mycetoma 

Malaria. concurrent infections, 
152; process of infection, 147; 
proof of infection, 113 

Mallein, 103 

Megaloblasts, 302 

Metabolism (see Nitrogenous 
metabolism; see Glycosuria), 
causes of changes in disease, 



429; in disease of nervous sys- 
tem, 494; in gastro-intestinal 
disease, 433 ; of carbohydrates, 
427; of fat, 428 

Methemoglobin, 323 

Methylguanidin, 73 

Microblasts, 302 

Mucin, characters of, 195 ; in mu- 
cinoid degeneration, 211 

Muscles, voluntary, action of 
suprarenal extract on, 421 ; ef- 
fect of nerve disease on, 483 ; 
fatty degeneration of, 205 

Mycetoma, 53 

Microcytes, 300 

Myelocyte, 309 

Mydalein, J2> 

Mytilotoxin, 74 

Myxedema, 411 

Necrosis, caseous and bacterial, 
217 ; causes of, 214 ; in inflam- 
mation, 11 

Nephrotoxin, 191 

Nerve cells, normal, 460; changes 
in, 461 

Nervous system (see also Neu- 
rons and Nerve cells), arrange- 
ment of, 457; causes of degen- 
eration of, 492 ; chemical changes 
in degeneration of, 468 ; effect of 
circulation on, 491 ; influence on 
respiration in disease, 288; 
metabolism in disease of, 494 

Neurin, 73 

Neurons, anatomical effects of in- 
jury to, 465 ; arrangement of 
projection systems, 459; condi- 
tions of nutrition of, 461 ; dis- 
eases of, 470; effects of diseases 
of, 483 

Nitrification, 71 

Nitrogenous metabolism (see also 
Uric acid), excretion of prod- 
ucts of, 398; general discussion 
of, 425 ; in anemias, 452 ; in 
cyanosis, 450; in jaundice, 375; 
in kidney disease, 394 ; in liver 
disease, 384; in pyrexia, 44; re- 
tention of products of, 396 

Normoblasts, 302 

Nucleo-proteids, in cells, 194; in 
cerebro-spinal fluid, 470; in co- 
agulation of blood, 331 ; metab- 
olism of, 437 

Obesity, changes in, 198; metab- 
olism in, 448 



INDEX 



5° r 



Oxalic acid, in urine, 400., 449 

Pancreas, extirpation of, 444; 
metabolism in disease of, 435 

Parasites, effects of animal, 50; in- 
fective. 51 ; non-infective, 51 

Pellagra, 408 

Periarteritis. See Arteries 

Pericardial disease, effect on cir- 
culation. 234 

Peripheral neuritis, 86, 471, 483 

Pernicious anemia (see also An- 
emias), blood in, 307; fatty de- 
generation in, 203 ; nerve degen- 
eration in. 480 

Pfeiffer's reaction. 187 

Phagocytosis, in immunity, 191, 
313 ; in infection. 31 ; patho- 
logical. 28 ; physiological, 27 

Phenol compounds, in urine, 404 

Pigmentation, causes of, 366; in 
inflammation, 12 ; of urine, 402 

Pituitary body, effects of removal 
of, 41/ 

Plague. See B. pestis 

Pneumococcus, characters of, 55 ; 
infection by, 118, 122 

Poikilocytosis, 300 

Polioencephalitis, 476 

Poliomyelitis, 476 

Polycythemia, 300 

Precipitins, 190 

Progressive muscular atrophy, 477 

Proteids. character of, 195 ; forma- 
tion of fat from, 199 

Proteid metabolism. 425. See also 
Nitrogenous metabolism 

Ptomains, 73 

Pulse. See Heart 

Purin bodies, 437 

Pus cocci (pyococci), character of, 
55 ; process of infection by, 122 

Putrefaction, bacteria of. 72 ; ex- 
cretion of products in urine, 
403; in intestine. 145; products 
of, 72 

Pyemia. See Pus cocci 

Pyrexia, causes of. 46 ; increase of 
cardiac rate in. 251 ; pathological 
changes in, 39; produced by an- 
thrax products, 78; produced by 
diphtheria products, 82; pro- 
duced by typhoid products, 94; 
symptoms in, 38; types of. 38 

Rabies (Hydrophobia), artificial 

immunity in. 172 
Reaction of degeneration, 483 



Red corpuscles, in disease, 300; 
normal, 298 

Regeneration of tissues, 227 

Respiration, causes of disordered, 
279; compensation in disordered, 
290 ; effect of diphtheria poison 
on, 84; metabolism in disorders 
of. 449 ; normal, 277 

Respiratory exchange, in anemias, 
452 ; in cyanosis, 450 ; in pyrexia, 

.3? 
Ricin, action of, 91 ; immunity by, 
177; necrosis produced by, 217 

Schizomycetes. See Bacteria. 

Septicemia, 125 

Snake venom, action of. 88 ; im- 
munity bv, 177. 181 ; toxicity of, 
108 

Sneezing, 296 

Spasm, 485. 490 

Spastic paraplegia, 475 

Spermatotoxin, 190 

Spleen, fibrosis of, 225 ; in im- 
munity, 164 ; in relation to leu- 
kocytes, 319 

Stomach, changes in metabolism 
in disease of, 435 

Suppuration. See Pus cocci 

Suprarenal bodies, action of ex- 
tract of, 421 ; results of extirpa- 
tion of, 420 

Syphilis, process of infection in, 
140, 493 

Syringomyelia, 482 

Tabes dorsalis. 477 

Temperature of the body, effect of 
bacterial products on, yy et seq.; 
maintenance of, 36 ; normal, 35 ; 
subnormal. 37 

Tetanus. See B. tetani 

Thermogenesis. 36 

Thermolysis, 36 

Thermotaxis, 36 

Thrombosis. 334; causes of. 341; 
results of, 348 

Thyroid gland, action of extract 
of, 414; disease of, 411 ; extirpa- 
tion of, 412 

Toxins, 74; from individual bac- 
teria, yy ; general action of, 104; 
relation to antitoxin, 179 

Tremor, 489 

Trichotoxin, 190 

Trophoneuroses (trophic 
changes), 487 



5° 2 



INDEX 



Tuberculin, 101 

Tuberculosis (see also B. tubercu- 
losis), process of infection in 
man, 127 ; in animals, 135 ; sec- 
ondary infection in, 139 

Typhoid fever. See B. typhosus 

Tyrotoxicon, 74 

Uremia, 393 

Urea, fermentation, 70. See also 
Nitrogenous metabolism 

Uric acid, in disease, 436, 455; in 
gout, 439; normal excretion of, 
398 ; origin of, 436 ; solubility of, 
438 

Urine, amount of water excreted. 
388, 400: aromatic substances in, 
403 ; effect of kidney disease on, 
390 ; in pyrexia, 45 ; normal 
composition of, 398 ; pigments in, 
402 ; specific gravity of, 401 ; sup- 
pression of, 387 ; toxicity of, 388 



Urobilin, from blood extravasa- 
tion, 364; from other sources, 
402 

Uroerythrin, 402 

Urohematoporphyrin, 402 

Vaccinia, immunity in, 165 

Venous pulse, 236 

Vibrio cholerae asiaticae, charac- 
ters of, 57; immunity by, 170; 
micro-organisms allied to, 59; 
process of infection by, in, 143; 
products of, 100; serum reaction 
with, 187 

Wallerian degeneration, 205, 

465, 47i 
White corpuscles. See Leukocytes 

Zenker's degeneration, 219 
Zymase, 70 



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